Cancer Biology

• Andrew Andrews
• Daniel Bassi
• Alfonso Bellacosa
• Jeff Boyd
• Kathy Cai
• Paul Cairns
• Xiaowei Chen
• Jonathan Chernoff
• Edna Cukierman
• Greg Enders
• Gary Hudes
• Richard Katz
• Andres Klein-Szanto
• Vladimir Kolenko
• Warren Kruger
• Alexander Kutikov
• Alla Lapidus
• Biao Luo
• Beatrice Mintz
• Alana O'Reilly
• Jeffrey Peterson
• Fabrice Roegiers
• Joseph Testa
• Natalia Tulina
• Alexei Tulin
• Robert Uzzo
• Zeng-jie Yang
• Hong Yan
• Tim Yen

Cancer Prevention and Control

• J. Robert Beck
• Wen-Chi Chang
• Margie Clapper
• Mary Daly
• Joanne Dorgan
• Efrat Dotan
• Carolyn Fang
• Linda Fleisher
• Michael Hall
• Carolyn Heckman
• Amy Lazev
• Suzanne Miller
• Camille Ragin
• Irma Russo
• Eric Ross
• Jose Russo
• Pamela Shapiro
• Kuang-Yi Wen
• Yu-Ning Wong

Developmental Therapeutics

• Gregory Adams
• Igor Astsaturov
• Hossein Borghaei
• Barbara Burtness
• Mark Buyyounouski
• Lili Chen
• Denise Connolly
• Mohan Doss
• Roland Dunbrack
• Brian Egleston
• Lori Goldstein
• Erica Golemis
• Elizabeth Hopper-Borge
• Eileen Jaffe
• C-M Charlie Ma
• Lainie Martin
• Ranee Mehra
• Mark Morgan
• Anthony Olszanski
• John Ridge
• Matthew Robinson
• Heinrich Roder
• Michael Seiden
• Elin Sigurdson
• Margaret von Mehren
• Jinhua Wu
• Dong-Hua Yang
• Anthony Yeung

Immune Cell Development and Host Defense

• Tahseen Al-Saleem
• Siddharth Balachandran
• Kerry Campbell
• Adam Cohen
• Richard Hardy
• Kyoko Hayakawa
• Dietmar Kappes
• Barbara Pro
• Glenn Rall
• Jennifer Rhodes
• Valentin Robu
• Christoph Seeger
• Luis Sigal
• Ann Skalka
• David Wiest

Research Summary

A cell contains two meters of DNA compacted 500,000-fold to fit in to the nucleus.  Histones play a key role in compacting chromosomal DNA, which represents a major obstacle for proteins that need to access that DNA. One of the main ways that histone-DNA interactions are regulated is by chemical modification histones.  The goal of my lab is to understand the link between the specificity of histone modifications and the impact of these modifications on chromatin dynamics, which directly affects gene expression.  While the correlation between histone PTMs and disease is well established there are still critical gaps in our understanding of this relationship.  The majority of histone modification enzymes can modify more than one location on a single histone, but little is known about how the location and extent of these modifications are regulated.  Histone chaperones can interact with both histone modification enzymes and histones, and are proposed to aid the determinion which histone residues are modified.  To determine how histone chaperones or other factors control which residue(s) on a histone become modified, my lab is pursuing two research aims: 

1. Determine the thermodynamic conditions which favor specific complexes between histones and histone-modifying enzymes; 
2. Develop experimental approaches that can monitor the post-translational modification of multiple residues as a function of time. A complimentary goal of my lab is to determine the impact of both single and multiple histone modifications on the thermodynamics of chromatin.

Selected Publications

1. Andrews AJ, Luger K. Nucleosome structure(s) and stability: Variations on a theme. Annual Reviews in Biophysics. Forthcoming 2010.
2. Andrews, A., and Luger, K. A Coupled equilibrium approach to study nucleosome thermodynamics, Biothermodynamics, Methods of Enzymology. Forthcoming 2010.
3. Andrews AJ, Chen X, Zevin A, Stargell LA, Luger K. The histone chaperone Nap1 promotes nucleosome assembly by eliminating nonnucleosomal histone DNA interactions. Mol Cell. 2010 Mar 26;37(6):834-42. PubMed
4. Park Y, Sudhoff K, Andrews A, Stargell L, Luger K. Histone chaperone specificity in Rtt109 activation. Nat Struct Mol Biol. 2008 Sep;15(9):957-64. 2. PubMed
5. Andrews AJ, Downing G, Brown K, Park YJ, Luger K. A thermodynamic model for Nap1 - histone interactions. J Biol Chem. 2008 Nov 21;283(47):32412-8. Epub 2008 Aug 25. PubMed
6. Geiss BJ, Thompson AA, Andrews AJ, Sons RL, Gari HH, Keenan SM, Peersen OB. Analysis of Flavivirus NS5 Methyltransferase Cap Binding. J Mol Biol. 2009 Feb 6;385(5):1643-54. Epub 2008 Dec 11. PubMed

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Ovarian Tumor Progression

My research interests center in determining the role of a family of nine serine proteases, the proprotein-convertases (PCs) in ovarian tumor progression.  Most PCs activate protein precursors after limited proteolysis at the consensus sequence RXR/KR. Many of these precursors are associated with tumor progression, such as growth factors and their receptors, metalloproteinases, and adhesion molecules, pointing to a PCs role in regulating tumor progression. For instance, increased expression of these PCs has been correlated with increase histopathological grade and advanced metastatic behavior.  

We have determined that increased furin, the prototype of the family, predicts poor survival in ovarian cancer, regardless the specific type of tumor. Moreover, specific blockage of its activity by protein inhibitors and siRNA technology resulted in decreased proliferation and signaling through the insulin-like receptor pathway. Interestingly, a closely related PC, PACE4, also associated with tumor progression in skin and other malignancies, showed an opposite effect in ovarian cancer; more benign and less malignant tumors expressed higher levels of this extracellular protease.  In this context, therapies aimed at decreasing ovarian tumor burden should address these differences to exploit this antagonistic effect exerted by these two proteases.

Selected Publications

1. Cukierman E, Bassi, DE. The mesenchymal tumor microenvironment: A drug-resistant niche. Cell Adh Migr. 2012 May 1;6(3):285-96. Epub 2012 May 1. PubMed
2. Bassi DE, Zhang J, Cenna J, Litwin S, Cukierman E, Klein-Szanto AJ. Proprotein Convertase Inhibition Results in Decreased Skin Cell Proliferation, Tumorigenesis, and Metastasis. Neoplasia. 2010 Jul;12(7):516-26. PubMed
3. Page RE, Klein-Szanto AJ, Litwin S, Nicolas E, Al-Jumaily R, Alexander P, Godwin AK, Ross EA, Schilder RJ, Bassi DE. Increased expression of the pro-protein convertasefurin predicts decreased survival in ovarian cancer. Cell Oncol. 2007;29(4):289-99. PubMed
4. Bassi DE, Lopez de Cicco R, Cenna J, Cukierman E, Klein-Szanto AJ. PACE 4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression. Cancer Res. 2005;65:7310-7319. PubMed
5. Bassi B, Lopez De Cicco R, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJ. Furin Inhibition Results in Absent or Decreased Invasiveness and Tumorigenicity of Human Cancer Cells. Proc Natl Acad Sci. (USA) 2001;98:10326-10331. PubMed

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DNA Repair in Cancer and Development

Our research is focused on the analysis of genetic and epigenetic alterations of cancer cells in an effort to understand normal gene function and pathogenesis of disease, with the ultimate goal of identifying critical regulatory molecules/pathways as targets for innovative approaches of cancer prevention and therapy. Mutations in cancer cells are often the consequence of defective DNA repair that leads to a situation of "genomic instability." We are particularly interested in the mammalian DNA repair enzymes that protect the integrity of CpG sequences in DNA. This is important because mutations at CpG sites represent about one third of all point mutations in cancer. In addition, CpG sites are also important for regulation of gene activity by an epigenetic process called DNA methylation. We found that alterations in DNA repair can also cause altered DNA methylation patterns at the level of CpG sites resulting in a situation of "epigenomic instability" that is incompatible with normal development. Importantly, alterations of DNA methylation are also very frequent in cancer. Thus, the goal of this research is to clarify how alterations in genomic and epigenomic stability of CpG sequences lead to altered development and cancer formation.

Selected Publications

1. Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, Abramowitz LK, Bartolomei MS, Rambow F, Bassi MR, Bruno T, Fanciulli M, Renner C, Klein-Szanto AJ, Matsumoto Y, Kobi D, Davidson I, Alberti C, Larue L, Bellacosa A. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011 146(1):67-79. PubMed
2. Bellacosa A, Godwin AK, Peri S, Devarajan K, Caretti E, Vanderveer L, Bove B, Slater C, Zhou Y, Daly M, Howard S, Campbell KS, Nicolas E, Yeung AT, Clapper ML, Crowell JA, Lynch HT, Ross E, Kopelovich L, Knudson AG. Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations. Cancer Prev Res. 2010 3(1):48-61. PubMed
3. Howard JH, Frolov A, Tzeng CW, Stewart A, Midzak A, Majmundar A, Godwin AK, Heslin MJ, Bellacosa A, Arnoletti P. Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer. Cancer Biology & Therapy. 2009 Jan;8(1):94-100. PubMed
4. Cortellino S, Wang C, Wang B, Bassi MR, Caretti E, Champeval D, Calmont A, Jarnik M, Burch J, Zaret KS, Larue L, Bellacosa A. Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4. Dev Biol. 2009 Jan 1;325(1):225-37. PubMed
5. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, Dargemont C, de Herreros AG, Bellacosa A, Larue L. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2007 26(53):7445-56. PubMed
6. Turner DP, Cortellino S, Schupp JE, Caretti E, Loh T, Kinsella TJ, Bellacosa A. The DNA N-glycosylase MED1 exhibits preference for halogenated pyrimidines and is involved in the cytotoxicity of 5-iododeoxyuridine. Cancer Res. 2006 66(15):7686-93. PubMed

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Molecular Genetics of Women's Cancers

Research in our laboratory is directed generally toward understanding the molecular genetics and genetics of women's cancers, specifically those of the ovary, endometrium, and breast. Past work has focused on genetic predisposition to these cancers, including the BRCA-related breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer syndrome (HNPCC or Lynch syndrome) and on defining the somatic molecular alterations relevant to the tumorigenic process in these sites. Currently, we are actively engaged in three projects: 1) studying the early natural history of ovarian cancer, especially the development of chromosomal abnormalities as a very early event in ovarian tumorigenesis; 2) defining the role of the CA125 biomarker (encoded by the MUC16 gene) in ovarian tumorigenesis; and 3) investigating a novel mechanism through which estrogen is carcinogenic at the molecular level, i.e., through the estrogen receptor-mediated silencing of critical tumor suppressor gene expression.

Selected Publications

1. Pothuri B, Leitao MM, Levine DA, Viale A, Olshen AB, Arroyo C, Bogomolniy F, Olvera N, Lin O, Soslow RA, Robson ME, Offit K, Barakat RR, Boyd J. Genetic analysis of the early natural history of ovarian carcinoma. PLoS ONE. 2010; e10358. PLoS ONE
2. Olshen AB, Gold B, Lohmueller KE, Struewing JP, Satagopan J, Stefanov SA, Eskin E, Kirchhoff T, Lautenberger JA, Friedman E, Norton L, Ellis NA, Viale A, Lee CS, Borgen PI, Clark AG, Offit K, Boyd J. Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping. BMC Genetics. 2008;9:14. PubMed
3. King TA, Li W, Brogi E, Yee CJ, Gemignani ML, Olvera N, Levine DA, Norton L, Robson ME, Offit K, Boyd J. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann Surg Oncol. 2007;14:2510-8. PubMed
4. Black D, Soslow RA, Levine DA, Tornos C, Chen SC, Hummer AJ, Bogomolniy F, Olvera N, Barakat RR, Boyd J. The clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma. J Clin Oncol. 2006;24:1745-53. PubMed
5. Jazaeri AA, Awtrey CS, Gadisetti CVR, Chuang YE, Khan J, Sotiriou C, Aprelikova O, Yee CJ, Zorn KK, Birrer MJ, Barrett CJ, Boyd J. Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res. 2005;11:6300-10. PubMed
6. Ferguson SE, Olshen AB, Viale A, Barakat RR, Boyd J. Stratification of intermediate risk endometrial cancer patients into groups at high- or low-risk for recurrence based on tumor gene expression profiles. Clin Cancer Res. 2005;11:2252-7. PubMed
7. King TA, Gemignani ML, Li W, Tan LK, Giri DD, Panageas KS, Bogomolniy F, Arroyo C, Olvera N, Robson ME, Offit K, Borgen PI, Boyd J. Aberrant progesterone receptor expression in breast epithelium of BRCA1 mutation carriers. Cancer Res. 2004;64:5051-3.

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Summary

My research work focuses in two main areas.  First, I am actively developing and improving a group of histopathology-related technologies to support basic and translational research projects involving cell signaling, molecular carcinogenesis and animal modeling.  These approaches include immunohistochemistry, quantitative image analysis using Aperio technology and AQUA (a automatic quantitation platform for immunohistochemistry), laser capture microdissection, and other technologies.  Second, I provide extensive histological and histopathological support, including interpretation of results generated in human and experimental animal tissues, to FCCC investigators.

My long-term research interests include understanding the molecular mechanism of ovarian cancer initiation and development. Research projects completed or in progress include quantitative image analysis of biomarkers on ovarian cancer tissue microarrays,  molecular characterization of initiation and progression of ovarian cancer, including aspects of the fallopian tube origin hypothesis, mouse modeling of ovarian cancer, and studies of early mouse embryonic development.

Selected Publications

1. Capo-chichi CD, Cai KQ, Simpkins F, Ganjei-Azar P, Godwin AK, Xu XX. Nuclear envelope structural defects cause chromosomal numerical instability and aneuploidy in ovarian cancer. BMC Med. 2011 Mar 26;9:28. Pubmed
2. Li H, Cai Q, Godwin AK, Zhang R. Enhancer of zeste homolog 2 (EZH2) promotes the proliferation and invasion of epithelial ovarian cancer cells. 2010. Mol Cancer Res. 2010 Dec;8(12):1610-8. Pubmed
3. Smith ER, Cai KQ, Smedberg JL, Ribeiro MM, Rula ME, Slater C, Godwin AK, Xu XX. Nuclear entry of activated MAPK is restricted in primary ovarian and mammary epithelial cells. PLoS One. 2010 Feb 18;5(2):e9295. Pubmed
4. Cai KQ, Caslini C, Capo-chichi CD, Slater C, Smith ER, Wu H, Klein-Szanto AJ, Godwin AK, Xu XX. Loss of GATA4 and GATA6 expression specifies ovarian cancer histological subtypes and precedes neoplastic transformation of ovarian surface epithelia. PLoS One. 2009 Jul 31;4(7):e6454. Pubmed
5. Capo-chichi CD, Cai KQ, Testa JR, Godwin AK, Xu XX. Loss of GATA6 leads to nuclear deformation and aneuploidy in ovarian cancer. Mol Cell Biol. 2009 Sep;29(17):4766-77. Pubmed
6. Cai KQ, Wu H, Klein-Szanto AJ, Xu XX. Acquisition of a second mutation of the Tp53 alleles immediately precedes epithelial morphological transformation in ovarian tumorigenicity. Gynecol Oncol. 2009 Jul;114(1):18-25. Pubmed
7. Cai KQ, Capo-Chichi CD, Rula ME, Yang DH, Xu XX. Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn. 2008 Oct;237(10):2820-9. Pubmed
8. Cai KQ, Yang WL, Capo-Chichi CD, Vanderveer L, Wu H, Godwin AK, Xu XX. Prominent expression of metalloproteinases in early stages of ovarian tumorigenesis. Mol Carcinog. 2007 Feb;46(2):130-43. Pubmed

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Research Summary

The field of epigenetics addresses the set of stable changes that influence gene expression patterns that do not arise from primary mutations in gene sequence. The primary focus of our research program is the translation of basic knowledge of the epigenetics of cancer to improve the early detection, prognosis, and prediction of response to treatment of cancer through novel and well-conceived molecular tests.

Cancer is a disease initiated and driven by the accumulation of genetic and epigenetic alterations of key genes acquired over a lifetime. These alterations can be used as targets for the detection of tumor cells in clinical specimens such as needle biopsies, or body fluids such as blood or urine. A molecular test that targets gene alterations at the DNA level has several conceptual advantages for the successful early detection of cancer. The alteration may be present, and therefore potentially detectable, before the cancer can be found by imaging or traditional pathology.  This is because either the alteration precedes overt cancer growth, or the abnormal cells represent a tiny fraction of the cell population in the biopsy. We pioneered methylation-based early detection of prostate, kidney and bladder cancer in urine, as well as ovarian and breast cancer in blood, and we are at the forefront of developing metrics for the more rapid and robust validation of molecular tests.

It is well known that patients with the same type and stage of cancer can have different outcomes. We are developing an aggressiveness index to predict how likely it is that a tumor will recur and progress or not, based on the epigenetic heterogeneity that underlies the different behavior of each person’s tumor. The ultimate goal is to simultaneously detect a cancer at an early curable stage, and to predict the best management based on the potential of the cancer to progress.

As we uncover the genes that are altered in cancer, we are investigating if epigenetic silencing of genes with a strong biological rationale can be used to predict a better or worse response to particular therapies. At present, we cannot predict whom a specific type of chemotherapy will work for. If we could identify, ahead of time, the people who will show a poor response, oncologists could give additional or different treatment. Epigenetic alterations are potentially reversible by treatment with certain drugs; hence, it may be possible to restore the sensitivity of a tumor to a standard chemotherapy.

Selected Publications

1. Banumathy G, Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 2010 Oct 4;10(7). [Epub ahead of print]. PubMed
2. Ibragimova I, Ibáñez de Cáceres I, Hoffman AM, Potapova A, Dulaimi E, Al-Saleem T, Hudes GR, Ochs MF, Cairns P. Global reactivation of epigenetically silenced genes in prostate cancer. Cancer Prev Res (Phila). 2010 Sep;3(9):1084-92. PubMed
3. Diamandis EP, Sidransky D, Laird PW, Cairns P, Bapat B. Epigenomics-based diagnostics. Clin Chem. 2010 Aug;56(8):1216-9. PubMed
4. Cairns P. 5'-azacytidine expression arrays. Methods Mol Biol. 2009;507:165-74. PubMed
5. Brooks, J. Cairns, P., Zeleniuch-Jacquotte, A. Promoter methylation and the detection of breast cancer. Cancer Causes Control. 2009 Nov;20(9):1539-50. PubMed
6. Potapova A, Hoffman AM, Godwin AK, Al-Saleem T, Cairns P. Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer Res. 2008 Feb 15;68(4):998-1002. PubMed
7. Cairns P. Gene methylation and early detection of genitourinary cancer: the road ahead. Nat Rev Cancer. 2007 Jul;7(7):531-43. PubMed

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Breast Cancer Susceptibility and Heterogeneity in Premalignant Lesions

Breast Cancer Susceptibility and Heterogeneity in Premalignant Lesions

Ductal Carcinoma in Situ (DCIS) detection rates have dramatically increased because of the widespread use of screening mammography. However, understanding of the biology and clinical behavior of DCIS is still limited, and there is no accurate risk assessment currently available to determine which patients with DCIS are at the greatest risk of developing an invasive carcinoma in their lifetime. The focus of my laboratory is to apply genome-wide allele-specific expression (ASE) analysis to identify novel risk alleles for DCIS progression by studying intra-individual DCIS heterogeneity. Current research projects include: (1) Identification of novel breast cancer risk loci in a post-GWAS era by global differential allele-specific expression (DASE); (2) Role of long non-coding RNAs and other genetic factors in DCIS progression; (3) Evaluation of intra-individual heterogeneity in DCIS lesions; (4) Identification of novel serum biomarkers for breast cancer early detection. Our long-term research goal is to identify differences among normal, pre-malignant and cancerous breast tissue, determine their consequences, and use this information to improve patient care.

Selected Publications

1. Gao C, Devarajan K, Zhou Y, Slater CM, Daly MB, Chen X. Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome. BMC genomics 2012; 13: 570. PubMed
2. Chen X, Weaver J, Bove BA, Vanderveer LA, Weil SC, Miron A, Daly MB, Godwin AK. Allelic Imbalance in BRCA1 and BRCA2 Gene Expression Is Associated with an Increased Breast Cancer Risk. Hum Mol Genet. 2008;17:1336-48. PubMed
3. Chen X, Truong TT, Weaver J, Bove BA, Cattie K, Armstrong BA, Daly MB, Godwin AK. Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Human Mutation. 2006;27:427-35. PubMed
4. Chen X, Arciero CA, Wang C, Broccoli D, Godwin AK. BRCC36 is essential for IR-induced BRCA1 phosphorylation and nuclear foci formation. Cancer Res. 2006;66:5039-46. PubMed
5. Schilder RJ, Sill M W, Chen X, Darcy KM, Decesare SL, Lewandowski G, Lee RB, Arciero CA, Wu H, Godwin AK. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res. 2005;11:5539-48. PubMed

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Role of Protein Phosphorylation in Neoplastic Transformation

The process of neoplastic transformation can be conceptually divided into two components. The first of these, proliferative transformation, refers to the ability of transformed cells to bypass growth suppression signals, dividing when normal cells would not. The second, morphologic transformation, refers to loss of normal cytoskeletal architecture, often accompanied by decreased adhesion and acquisition of the ability to invade surrounding tissues. These two fundamental properties are intimately linked to one another, although experimentally they can be dissected apart through the use of mutant oncogenes and other abnormal signaling molecules. The overall focus this research is in uncovering the roles of protein phosphorylation in governing these two fundamental aspects of cancer biology.

Selected Publications

1. Arias-Romero LE, Villamar-Cruz O, Pacheco A, Kosoff R, Huang M, Muthuswamy SK, Chernoff J. A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene Forthcoming 2010. PubMed
2. Arias-Romero LE, Saha S, Villamar-Cruz O, Yip SC, Ethier SP, Zhang ZY, Chernoff J. Activation of Src by protein tyrosine phosphatase 1B Is required for ErbB2 transformation of human breast epithelial cells. Cancer Res. 2009;69:4582-8. PubMed
3. Allen JD, Jaffer ZM, Burgin S, Hofmann C, Sells MA, Derr-Yellin E, Michels EG, Bessler WK, Ingram DA, Chernoff J*, and Clapp DW.* p21-activated kinase 1 is required in mast cells for FceRI-mediated inflammatory responses. Blood. 2009;113:2695-705 *co-corresponding authors. PubMed
4. Dadke S, Cotteret S, Yip SC, Jaffer ZM, Haj F, Ivanov A, Rauscher F, Shuai K, Ng T, Neel BG, Chernoff J. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol. 2007;9:80-5. PubMed
5. Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR. An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase. Chem. Biol. 2008 15:322-31. PubMed

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Fibroblastic Tumor-Associated Stroma and its 3D Extracellular Matrix

In order to develop new approaches for treatment of aggressive cancers, it is necessary to attain a better understanding of their development and progression. One poorly studied aspect of tumorigenesis is the nature of tumor-stromal interactions. It has become clear that the tumor microenvironment (including stromal fibroblasts, infiltrating immune and inflammatory cells, blood and lymphatic vascular network, and the extracellular matrix) is an integral part of the carcinogenic process promoting cell growth and metastases. Benign epithelial tumors are constrained by a surrounding stroma consisting of fibroblastic cells and a fibrillar three-dimensional extracellular matrix. These ‘normal’ fibroblasts and their matrices assist in maintaining a homeostatic equilibrium, exerting an inhibitory effect on the epithelial cells undergoing malignant changes. However, tumor-generated paracrine signaling alters and overcomes this stromal barrier, inducing changes in the local mesenchymal microenvironment that promote rather than impede tumor progression.

In our laboratory, we isolate primary fibroblasts from various murine and human cancers at different stages of tumorigenesis. Using these fibroblasts, we have developed a three-dimensional in vivo-like stromal system, which is used to conduct our studies. Research is directed at better understanding the role of tumor-associated stroma in cancer invasion and metastasis. We aim to understand how tumor cells alter the local mesenchymal microenvironment, at both primary and secondary (e.g., metastatic) niches, in a way that this stroma supports and incites (instead of constraining) tumor progression (e.g., cancer cell invasion). Our group also uses this three-dimensional culturing system as an approach to improve the preclinical cancer drug-development process, believing that stromal microenvironment can significantly alter the efficacy of drugs in evaluation or currently in use for cancer treatment. For this, our laboratory is carrying out analyses that incorporate biochemical, molecular and cell biology assays, laser scanning confocal and real time microscopy, digital analyses, as well as tissue patterning approaches.

Selected Publications

1. Håkanson M, Kobel S, Lutolf MP, Textor M, Cukierman E*, Charnley M*. Controlled Breast Cancer Microarrays for the Deconvolution of Cellular Multilayering and Density Effects upon Drug Responses. PLoS ONE 2012;7(6): e40141. doi:10.1371/journal.pone.0040141 (*co-corresponding author). PLoS ONE
2. Gupta V, Bassi DE, Simons JD, Devarajan K, Al-Saleem T, Uzzo RG, Cukierman E. Elevated expression of stromal palladin predicts poor clinical outcome in renal cell carcinoma. PLoS One. 2011;6(6):e21494. Epub 2011 Jun 28. PubMed
3. Goetz JG, Minguet S, Navarro-Lérida I, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibáñez T, Pellinen T, Echarri A, Cerezo A, Klein-Szanto AJ, Garcia R, Keely PJ, Sánchez-Mateos P, Cukierman E, Del Pozo MA. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011 Jul 8;146(1):148-63. PubMed
4. Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E*, Cheng JD*. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer. 2011 Jun 13;11(1):245. (* co-corresponding author). PubMed
5. Kwon Y, Cukierman E*, Godwin AK*. Differential expressions of adhesive molecules and proteases define mechanisms of ovarian tumor cell matrix penetration/invasion. PLoS One. 2011 Apr 19;6(4):e18872. (* co-corresponding author). PubMed
6. Castelló-Cros R, Khan DR, Simons J, Valianou M, Cukierman E. Staged stromal extracellular 3D matrices differentially regulate breast cancer cell responses through PI3K and beta1-integrins. BMC Cancer. 2009 Mar 26;9:94. PubMed
7. Serebriiskii I, Castello-Cros R, Lamb A, Golemis EA, and Cukierman E. Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells. Matrix Biology. 2008;27:573-585. PubMed
8. Amatangelo MD, Bassi DE, Klein-Szanto AJ, Cukierman E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am J Pathol. 2005;167(2):475-88. PubMed
9. Cukierman E, Pankov R, Stevens DR, and Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001;294:1708-1712. PubMed

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Regulation of the Mammalian Cell Division Cycle and Gastrointestinal Tumorigenesis

Our program focuses on a key family of enzymes, termed cyclin dependent kinases (Cdks), that drive successive steps of cell duplication. Activation of these enzymes is needed for every cell to divide. Deregulation of Cdks contributes to cancer development, because it allows cells to duplicate uncontrollably. Conversely, inhibition of Cdks suppresses cancer by preventing cells from duplicating. Our research spans the spectrum from clinical to basic research, using patient tissue samples, mouse models, and biochemical studies. Themes include the effects of Cdks on stem cells (which duplicate to replace lost cells), and on cellular senescence (the process that causes older cells to stop duplicating). A goal is to identify how Cdk function and regulation in tumor cells differs from that in normal cells and to take advantage of these differences in cancer prevention and therapy.

Selected Publications

1. Li C, Andrake M, Dunbrack R, Enders GH. A bi-functional regulatory element in human somatic Wee1 mediates cyclin A/Cdk2 binding and Crm1-dependent nuclear export. Molecular and Cellular Biology. 2010;30:116-30.
2. Boquoi A, Jover R, Chen T, Pennings M, Enders G. Transgenic expression of VEGF in intestinal epithelium drives mesenchymal cell interactions and epithelial neoplasia. Gastroenterology. 2009 Feb;136(2):596-606.e4. PubMed
3. Gibson SL, Dai CY, Lee HW, DePinho RA, Gee MS, Lee WM, Furth EE, Brensinger C, Enders GH. Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus. Cancer Research 2003 Feb 15;63(4):742-6. PubMed
4. Hu B, Mitra J, Van den Heuvel S, Enders GH. S and G2 phase roles for Cdk2 revealed by inducible expression of a dominant-negative mutant in human cells. Molecular & Cellular Biology 2001 Apr;21(8):2755-66. PubMed
5. Dai CY, Enders GH.: p16 INK4a can initiate an autonomous senescence program. Oncogene 2000 Mar 23;19(13):1613-22. PubMed

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Research Interests

Our primary goal is to develop more effective treatment for advanced prostate cancer, a disease responsible for 40,000 deaths annually. We have performed a series of clinical trials based on the hypothesis that drugs with complementary targets within the microtubule complex of cells can be combined to produce more effective prostate cancer treatment. In support of this hypothesis, our previous studies have demonstrated that combinations of estramustine with either paclitaxel or vinblastine produce regression of metastases in approximately half of patients with hormonally-resistant prostate cancer (HRPC). Our current efforts are aimed at improving the extent and duration of tumor regression, and reducing the toxic effects of treatment. In two recently completed studies, we have shown that 1) intravenous (i.v.) estramustine can be administered safely at doses much higher than were previously thought possible, and 2) weekly administration of paclitaxel with reduced, intermittent doses of oral estramustine is better tolerated and at least as effective as the more cumbersome and toxic continuous administration of estramustine and paclitaxel.

To build upon these encouraging results, it will be necessary to identify new drugs that block prostate cancer growth and that can be added to our current combination therapies without causing excessive toxicity. In the past year, we have completed a phase I clinical trial of R115777, an orally administered methylquinone and potent inhibitor of the enzyme, farnesyl protein transferase (FPTase). Importantly, we have seen antitumor effects in patients with HRPC, thus making R115777 and other inhibitors of FPTase logical candidates for further study in patients with HRPC.

A premise of our research program is that progress in the chemotherapy of prostate cancer and other malignancies will depend on rational incorporation of agents that modify cell signaling and gene expression in a manner that promotes programmed cell death, modulates stress response, or modifies cell cycle progression to enhance the actions of traditional cytotoxic drugs.

Selected Publications

1. Ibragimova I, de Caceres, Hoffman AM, Potapova A, Dulaimi E, Al-Saleem T, Hudes GR, Ochs MF, Cairns P. Global Reactivation of Epigenetically Silenced Genes in Prostate Cancer. Cancer Prevention Research. 2010 Sep;3(9):1084-92.
2. Pei J, Feder MM, Al-Saleem T, Liu Z, Liu A, Hudes GR, Uzzo RG, Testa JR. Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma. Genes Chromosomes Cancer. 2010 Jul;49(7):610-9.
3. Motzer RJ, Hudes GR, Ginsberg MS, Baum MS, Harmon CS, Kim ST, Chen I, Redman BG. Phase I/II Trial of Sunitinib Plus Gefitinib in Patients With Metastatic Renal Cell Carcinoma. American Journal of Clinical Oncology-Cancer Clinical Trials. 2010 Dec;33(6):614-8.
4. Sridhar SS, Hotte SJ, Chin JL, Hudes GR, Gregg R, Trachtenberg J, Wang LS, Tran-Thanh D, Pham NA, Tsao MS, Hedley D, Dancey JE, Moore MJ. A Multicenter Phase II Clinical Trial of Lapatinib (GW572016) in Hormonally Untreated Advanced Prostate Cancer. American Journal of Clinical Oncology-Cancer Clinical Trials. 2010 Dec;33(6):609-13.
5. Zbrozek AS, Hudes G, Levy D, Strahs A, Berkenblit A, DeMarinis R, Parasuraman S. Q-TWiST Analysis of Patients Receiving Temsirolimus or Interferon Alpha for Treatment of Advanced Renal Cell Carcinoma. Pharmacoeconomics. 2010;28(7):577-84.

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Epigenetic Regulation in Cancer and Normal Cells

Our research focuses on the epigenetic control of gene expression. Epigenetics is the study of inherited changes in gene expression or cell phenotype that are independent of DNA sequence, but rather, are controlled by modifications to chromatin. The most dramatic example of epigenetic control is the specialization of cells that occurs during embryonic development and adult cell differentiation, whereby the DNA in each cell is largely identical, but specific genes sets are switched on or off. These on-off gene states are “memorized” through many cell divisions. Errors in this process can lead to a variety of diseases, including cancer. “Epigenetic gene silencing” refers to the heritable shut-off of genes. The two major mechanisms that underlie epigenetic silencing are DNA methylation and histone modifications, and hundreds of factors participate in initiating and maintaining these modifications on chromatin. Inappropriate gene silencing can lead to cancer and other diseases, but unlike gene inactivation due to mutations, epigenetic gene silencing is reversible. One goal of our research is to identify networks and novel cellular factors that maintain epigenetic gene silencing, such that new therapies can be devised to reactivate critical genes. Furthermore, as epigenetic mechanisms control cellular identity and plasticity, we are investigating strategies whereby cancer cells can be returned to a normal state.

The projects being carried out in our laboratory address the fundamental roles of epigenetic silencing factors, and their relevance to cancer and other diseases. First, we have developed and implemented a high throughput siRNA screen to functionally probe each cellular factor for its participation in epigenetic processes. Second, we are investigating the roles of epigenetic regulation in the plasticity of cancer cells. Third, as retroviral DNA can be inactivated by the host cell epigenetic silencing machinery, we are using these viruses as robust probes to study the silencing process. Lastly, we are investigating how certain dietary compounds may provide chemopreventive effects by influencing epigenetic events.  

Selected Publications

1. Poleshko A, Shalginskhih N, Katz RA. Functional networks of human epigenetic factors. In: Epigenomics: From Chromatin Biology to Therapeutics (Appasani, K., ed.). Cambridge University Press, in press.
2. Poleshko A, Einarson MB, Adams PD, Zhang R, Skalka AM, Katz RA. Identification of a functional network of human epigenetic silencing factors. J. Biol Chem. 2010;285:422-33, Epub 2009 Oct 30. PubMed
3. Frescas D, Guardavaccaro D, Kuchay SM, Kato H, Poleshko A, Basrur V, Elenitoba-Johnson KS, Katz RA, Pagano M. KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state. Cell Cycle. 2008;7:3539-47. PubMed
4. Poleshko A, Palagin I, Zhang R, Boimel P, Castagna C, Adams PD, Skalka AM, Katz RA. Identification of cellular proteins that maintain retroviral epigenetic silencing: evidence for an antiviral response. J Virol. 2008;82:2313-23. PubMed

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Research Overview

Tumor progression is a chain of cellular and molecular events that occur gradually during the development of neoplasia. We are studying the role of pro-protein convertases (PCs) such PACE-4 and furin during the early and late stages of tumor progression because these enzymes activate cancer related biomolecules. Over-expression of PCs correlates with aggressive tumor features both in mouse models and in human tumors. This has been demonstrated in our laboratory using tumor cells derived from lung, ovarian and oral malignant tumors. Inhibition of PCs can be obtained by using competitive inhibitors such as chloro-methyl-ketone (CMK). This inhibitor decreases and even abolishes the invasive/malignant phenotype of tumor cells by inhibiting the activation of invasion and metastasis-associated gene products such as MT1-MMP, stromelysin 3, TGF-β and IGFR1. CMK was also used in vivo by topical skin administration. Using this modality we were able to decrease 40% the number of chemically-induced mouse skin cancers as well as diminish 60% the respective tumor volumes.

Another unrelated gene, discovered during our PCs studies is Vsnl-1, a member of the neuronal Ca++ sensor protein family. Vsnl-1, also known as VILIP-1 is able to act as a tumor suppressor in mouse skin squamous carcinoma cells by inhibiting cell proliferation, adhesion and invasion. The effects are a consequence of VILIP-1 modulating cAMP levels as well as inactivating MMP-9 and RhoA activity. Recently, we have found that this gene is silenced in human tumors due to epigenetic changes including promoter hypermethylation and histone modification.

Selected Publications

1. Fu J, Bassi DE, Zhang J, Li T, Nicolas E, Klein-Szanto AJ. Transgenic overexpression of the proprotein convertase furin enhances skin tumor growth. Neoplasia. 2012 Apr;14(4):271-82. PubMed
2. Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, Abramowitz LK, Bartolomei MS, Rambow F, Bassi MR, Bruno T, Fanciulli M, Renner C, Klein-Szanto AJ, Matsumoto Y, Kobi D, Davidson I, Alberti C, Larue L, Bellacosa A. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011 Jul 8;146(1):67-79. PubMed
3. Goetz JG, Minguet S, Navarro-LeridaI, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibanez T, Pellinen T, Echarri A, Klein-Szanto A.J, Garcia R, Keely P, Sanchez-Mateos P, Cukierman E, Del Pozo MA. Regulation of the biomechanical properties of the tumor microenvironment by stromal Caveolin-1 promotes invasion. Cell. 2011;146:148-63.
4. Stairs, DB, Bayne L, Rhoades B, Vega ME, Waldron T, Kalabis J, Klein-Szanto AJ, Lee S, Katz J, Diehl A, Reynolds A, Vonderheide R, Rustgi AK. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a bona fide tumor suppressor. Cancer Cell 19, 470-483, 2011.
5. Schonrath K, Pan W, Klein-Szanto AJ, Braunewell KH. Involvement of VILIP-1 and opposite roles of cyclic AMP and GMP signaling in in vitro cell migration of murine skin squamous cell carcinoma. Molec. Carcinogenesis 50:319-333, 2011.
6. Bassi DE, Zhang J, Cenna J, Litwin S, Cukierman E, Klein-Szanto AJ. Proprotein Convertase Inhibition Results in Decreased Skin Cell Proliferation, Tumorigenesis, and Metastasis. Neoplasia. 2010 Jul;12(7):516-26. PubMed
7. Fu J, Jin F, Zhang J, Fong K, Bassi DE, Lopez De Cicco R, Ramaraju D, Braunewell KH, Conti C, Benavides F, Klein-Szanto AJ. VILIP-1 Expression /In Vivo/ Results in Decreased Mouse Skin Keratinocyte Proliferation and Tumor Development. PLoS One. 2010 Apr 15;5(4):e10196. PubMed
8. Fu J, Zhang J, Jin F, Patchefsky J, Braunewell KH, Klein-Szanto AJ. Promoter regulation of the visinin-like subfamily of neuronal calcium sensor proteins by nuclear respiratory factor-1. J Biol Chem. 2009 Oct 2;284(40):27577-86. PubMed
9. Braunewell K-H & Klein-Szanto AJ. Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca(2 )-sensor proteins. Cell Tissue Res. 2009;335:301-316. PubMed
10. Fu J, Fong K, Bellacosa A, Ross E, Apostolou S, Bassi D, Jin F, Zhang J, Cairns P, Iba�ez de Caceres I, Braunewell K, Klein-Szanto AJ. VILIP-1 Downregulation in Non-Small Cell Lung Carcinomas: Mechanisms and Prediction of Survival. PLoS ONE. 2008;3:(2)e1698. PubMed
11. L�pez de Cicco R, Bassi D, Benavides F, Conti CJ, Klein-Szanto AJ. Inhibition of Proprotein Convertases: Approaches to Block Squamous Carcinoma Development and Progression. Molec Carcinog. 2007;46:654-659. PubMed
12. L�pez de Cicco R, Bassi DE, Zucker S, Seidah NG, Klein-Szanto AJ. Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res. 2005;65:4162-71. PubMed
Bassi DE, Lopez de Cicco R, Cenna J, Cukierman E, Klein-Szanto AJ. PACE 4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression. Cancer Res. 2005;65:7310-7319. PubMed
13. Bassi B, Lopez De Cicco R, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJ. Furin Inhibition Results in Absent or Decreased Invasiveness and Tumorigenicity of Human Cancer Cells. Proc Natl Acad Sci. (USA) 2001;98:10326-10331. PubMed
14. Click for a full list of Dr. Klein-Szanto's publications

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Research Summary

Our research efforts span the basic and the clinical sciences. In the laboratory, our work focuses on understanding the process of renal and prostatic carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers. As part of our work, we explore the role of zinc in development and progression of prostate malignancy.  Zinc concentrations diminish early in the course of prostate carcinogenesis -- prior to histopathological changes -- and continue to decline during progression toward castration-resistant growth.  The objective of research in our laboratory is to test and advance an emerging paradigm that intracellular zinc deficiency augments malignant potential of prostate cancer cells and, therefore, promotes prostate tumorigenesis. We are also investigating the role of zinc chelators as potential therapeutic agents for the treatment of castration-resistant prostate cancer. Findings from our laboratory indicate that treatment of prostate cancer cells with the zinc-chelating agent TPEN induces selective down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to cytotoxic agents.  Importantly, the observed effect is not limited to prostate cancer, as TPEN reduces expression of XIAP in malignant cell lines of various origins, including colon, ovarian, leukemia, breast and cervical cancer.  

The second major theme of our research is to determine the mechanism of tyrosine kinase inhibitor (TKIs)-resistance in genitourinary tumors. Our studies reveal that TKI-resistance coincides with the loss of phosphatase and tensin homolog (PTEN) protein expression in prostate and renal malignant cells. Conversely, expression of PTEN sensitizes prostate and renal tumors to multi-targeted tyrosine kinase inhibitor sunitinib both in vitro and in vivo. In addition, our studies indicate that an increase in expression of IL-6 and IL-8 correlates with sunitinib and pazopanib resistance in prostate and renal tumor cells.  Development of reliable biomarkers for TKI responses would be beneficial both in the clinical and in the research settings. Our recent studies are also exploring the therapeutic potential of piperine and piperlongumine, alkaloids isolated from black and long pepper, for primary and secondary prevention of urologic malignancies.  In the clinical arena, we focus our efforts on investigating the biology and natural history of small renal masses, addressing quantification of competing risks of death for patients with urologic malignancies, and improving reporting and risk-stratification of surgical outcomes for patients with kidney cancer.  

Selected Publications

1. Golovine K, Uzzo RG, Makhov P, Crispen PL, Kunkle D, Kolenko VM. Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-κB dependent pathway. Prostate. 2008 Sep 15;68(13):1443-9. PubMed
2. Makhov P, Golovine K, Uzzo RG, Rothman J, Crispen PL, Shaw T, Scoll BJ, Kolenko VM. Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis (XIAP) and sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Cell Death and Differentiation. Cell Death Differ. 2008 Nov;15(11):1745-51. PubMed
3. Golovine K, Makhov P, Uzzo RG, Shaw T, Kunkle D, Kolenko VM. Overexpression of the zinc uptake transporter hZIP1 inhibits NF-κB and reduces the malignant potential of prostate cancer cells in vitro and in vivo. Clin Cancer Res. 2008 Sep 1;14(17):5376-84. PubMed
4. Makhov P, Golovine K, Uzzo RG, Wuestefeld T, Scoll BJ, Kolenko VM. Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells. Gene. 2009 Feb 15;431(1-2):39-46. PubMed
5. Golovine K, Makhov P, Uzzo RG, Kutikov A, Kaplan DJ, Fox E, Kolenko VM. Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-kappaB-independent, proteasome-mediated mechanism. Mol Cancer. 2010 Jul 9;9:183. PubMed

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Genetic defects in methionine and amino acid metabolism and cancer

Amino acids are the building blocks of proteins and other important biological molecules. The sulfur containing amino acid methionine is especially interesting as alterations in methionine metabolism and methionine-related pathways are found in many human diseases (Figure 1), including rare inborn errors of metabolism to common diseases such as cardiovascular disease and cancer. Currently there are three major projects in the lab. Two concern particular methionine metabolic genes, cystathionine beta-synthase (CBS) and methylthioadenosine phosphorylase (MTAP). A third project is related to understanding how alterations in amino acid metabolism contributes to renal cell carcinoma.

Selected Publications

1. Gupta S, Kühnisch J, Mustafa A, Lhotak S, Schlacterman A, Slifker MJ, Klein-Szanto AJ, High KA, Austin RC, Kruger WD. Mouse models of cystathionine β-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia. FASEB J. 2009 Mar;23(3):883-93. PubMed
2. Singh LR, Kruger WD. Functional rescue of mutant human cystathionine β synthase by manipulation of Hsp26 and Hsp70 levels in Saccharomyces cerevisiae. J Biol Chem. 2009;284:4238-45. PubMed
3. Mustafa A, Kruger WD. Suppression of tumor formation by a cyclooxygenase-2 inhibitor and a peroxisome proliferator-activated receptor γ agonist in an in vivo mouse model of spontaneous breast cancer. Clin Cancer Res. 2008;14:4935-42. PubMed
4. Singh LR, Gupta S, Honig N, Kraus JP, Kruger WD. Activation of mutant enzyme function by proteasome inhibitors and treatments that induce Hsp70. PLOS Genetics Jan;6(1):e1000807, 2010.
5. Kadariya Y, Yin B, Tang BQ, Shinton SA, Quinlivan EP, Hua X, Klein-Szanto A, Al-Saleem TI, Bassing CH, Hardy RR, Kruger WD. Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma. Cancer Res. 2009 Jul;69(14):5961-9.

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Research Interests

In collaboration with Vladimir Kolenko, MD, PhD and Robert Uzzo, MD, our research efforts span the basic and the clinical sciences. Our work focuses on understanding the process of renal and prostatic carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers.

As part of our work, we explore the role of zinc in development and progression of prostate malignancy.  Zinc concentrations diminish early in the course of prostate carcinogenesis -- prior to histopathological changes -- and continue to decline during progression toward castration-resistant growth.  The objective of research in our laboratory is to test and advance an emerging paradigm that intracellular zinc deficiency augments malignant potential of prostate cancer cells and, therefore, promotes prostate tumorigenesis. We are also investigating the role of zinc chelators as potential therapeutic agents for the treatment of castration-resistant prostate cancer. Work performed by Dr. Kolenko indicates that treatment of prostate cancer cells with the zinc chelating agent TPEN induces selective down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to cytotoxic agents.  Importantly, the observed effect is not limited to prostate cancer, as TPEN reduces expression of XIAP in malignant cell lines of various origins e.g. colon, ovarian, leukemia, breast and cervical.

The second major theme of our research is to determine the mechanism of tyrosine kinase inhibitor (TKIs)-resistance in genitourinary tumors. Our studies reveal that TKI-resistance coincides with the loss of phosphatase and tensin homolog (PTEN) protein expression in prostate and renal malignant cells. On the contrary, expression of PTEN sensitizes prostate and renal tumors to multi-targeted tyrosine kinase inhibitor sunitinib both in vitro and in vivo. In addition, our studies indicate that an increase in expression of IL-6 and IL-8 correlates with sunitinib and pazopanib resistance in prostate and renal tumor cells.  Use of a reliable biomarker for TKI response, harbors promise both in the clinical and in the research settings.

In the clinical arena, we focus our efforts on addressing quantification of competing risks of death for patients with urologic malignancies, investigating the biology and natural history of small renal masses, improving reporting and risk-stratification of surgical outcomes for patients with kidney cancer, and addressing clinical approaches to patients with adrenal cancers and incidental adrenal masses.   

Selected Publications

1. Smaldone MC, Egleston BL, Uzzo RG, Kutikov A. Does Partial Nephrectomy Result in a Durable Overall Survival Benefit in the Medicare Population? Journal of Urology, in press.
2. Kutikov A, Egleston BL, Canter D, Smaldone MC, Wong YN, Uzzo RG. Competing Risks of Death in Patients with Localized Renal Cell Carcinoma: A Comorbidity Based Model. Journal of Urology, in press.
3. Kutikov A, Cooperberg MR, Paciorek AT, Uzzo RG, Carroll PR. Evaluating Prostate Cancer Mortality and Competing Risks of Death in Patients with Localized Prostate Cancer Using a Comprehensive Nomogram. Prostate Cancer and Prostatic Diseases, in press.
4. Simhan J, Smaldone MC, Canter DJ, Zhu F, Starkey R, Stitzenberg KB, Uzzo RG, Kutikov A. Trends in Regionalization of Adrenalectomy to Higher Volume Surgical Centers. Journal of Urology, 2012, in press.
5. Golovine KV, Makhov PB, Teper E, Kutikov A, Canter D, Uzzo RG, Kolenko VM. Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells. Prostate, Epub ahead of print, May 2012.
6. Makhov P, Golovine K, Kutikov A, Teper E, Canter DJ, Simhan J, Uzzo RG, Kolenko VM. Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells. Mol Cancer Ther. Epub head of print, April 2012.
7. Reyes J, Canter D, Putnam S, Simhan J, Smaldone MC, Kutikov A, Viterbo R, Chen DY, Uzzo RG. Thermal ablation of the small renal mass: Case selection using the R.E.N.A.L-Nephrometry Score. Urol Oncol. Epub ahead of print, April 2012.
8. Simhan J, Smaldone MC, Tsai KJ, Li T, Reyes JM, Canter D, Kutikov A, Chen DY, Greenberg RE, Uzzo RG, Viterbo R. Perioperative outcomes of robotic and open partial nephrectomy for moderately and highly complex renal lesions. Journal of Urology, Epub ahead of print, April 2012.
9. Klayton T, Price R, Buyyounouski MK, Sobczak M, Greenberg R, Li J, Keller L, Sopka D, Kutikov A, Horwitz EM. Prostate Bed Motion during Intensity-Modulated Radiotherapy Treatment. Int J Radiat Oncol Biol Phys. Epub ahead of print. Feb. 2012.
10. Long CJ, Canter DJ, Kutikov A, Li T, Simhan J, Smaldone M, Teper E, Viterbo R, Boorjian SA, Chen DY, Greenberg RE, Uzzo RG. Partial nephrectomy for renal masses ≥7cm: technical, oncological and functional outcomes. BJU Int., 2012, epub ahead of print.
11. Canter D, Kutikov A, Manley B, Egleston B, Simhan J, Smaldone M, Teper E, Viterbo R, Chen DY, Greenberg RE, Uzzo RG. Utility of the R.E.N.A.L. Nephrometry Scoring System in Objectifying Treatment Decision-making of the Enhancing Renal Mass. Urology. 2011, 78, 1089.
12. Kutikov A, Rozenfeld B, Egleston BL, Sirohi M, Hwang RW, Uzzo RG. Academic Ranking Score: A Publication-Based Reproducible Metric of Thought Leadership in Urology. European Urology, 2012, 61, 435.
13. Simhan J, Canter D, Teper E, Smaldone MC, Patil N, Patchefsky A, Guttman MC, Milestone BN, Wong YN, Hicks LA, Uzzo RG, Kutikov A. Adrenocortical Carcinoma Masquerading as a Benign Adenoma on CT Washout Study. Urology 2012, 79, e19.
14. Makhov PB, Golovine KV, Kutikov A, Canter DJ, Rybko VA, Roshchin DA, Matveev VB, Uzzo RG, Kolenko VM. Reversal of epigenetic silencing of AP-2alpha results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells. Carcinogenesis, 2011, 32, 1773.
15. Canter D, Kutikov A, Uzzo RG. How Chester Alan Arthur 'brightened' from a political spoilsman to a civil service reformer. BJU International, 2011, 108, 1235.
16. Canter D, Kutikov A, Golovine K, Makhov P, Simhan J, Uzzo RG, Kolenko VM. Are All Multi-targeted Tyrosine Kinase Inhibitors Created Equal? Canadian Journal of Urology, 2011, 18, 5819. – corresponding author
17. Makhov P, Golovine K, Canter D, Kutikov A, Simhan J, Corlew MM, Uzzo RG, Kolenko VM. Co-Administration of Piperine and Docetaxel Results in Improved Anti-Tumor Efficacy via Inhibition of CYP3A4 Activity. Prostate, 2012, 72, 661.
18. Klayton TL, Ruth K, Horwitz EM, Uzzo RG, Kutikov A, Chen DY, Sobczak M, Buyyounouski MK. Young age under 60years is not a contraindication to treatment with definitive dose escalated radiotherapy for prostate cancer. Radiother Oncol. 2011, 101, 508.
19. Kutikov A, Makhov P, Golovine K, Sirohi M, Street R, Canter DJ, Uzzo RG, Kolenko VM. Interleukin-6: A Potential Biomarker of Resistance to Multitargeted Receptor Tyrosine Kinase Inhibitors in Castration-Resistant Prostate Cancer. Urology, 2011, 78, 968.e7.
20. Canter D, Egleston B, Wong YN, Smaldone MC, Simhan J, Greenberg RE, Uzzo RG, Kutikov A. Use of radical cystectomy as initial therapy for the treatment of high-grade T1 urothelial carcinoma of the bladder: A SEER database analysis. Urol Oncol. 2011, Epub ahead of print.
21. Simhan J, Smaldone MC, Tsai KJ, Canter DJ, Li T, Kutikov A, Viterbo R, Chen DY, Greenberg RE, Uzzo RG. Objective Measures of Renal Mass Anatomic Complexity Predict Rates of Major Complications Following Partial Nephrectomy. European Urology, 2011, 60, 724.
22. Canter D, Simhan J, Wu KN, Uzzo RG, Kutikov A. Intensely PET-Avid Benign Adrenal Adenoma. Urology, 2011, 78, 1307.
23. Canter D, Kutikov A, Horwitz EM, Greenberg RE. Transrectal implantation of electromagnetic transponders following radical prostatectomy for delivery of IMRT. Can J Urol. 2011, 18, 5844.
24. Kutikov A, Smaldone MC, Egleston BL, Manley BJ, Canter DJ, Simhan J, Boorjian SA, Viterbo R, Chen DYT, Greenberg RE, Uzzo RG. Anatomic Features of Enhancing Renal Masses Predict Malignant and High-Grade Pathology: A Preoperative Nomogram using the RENAL Nephrometry Score. European Urology, 2011, 60, 241.
25. Kutikov A, Mallin K, Canter D, Wong YN, Uzzo RG. Effects of increased cross-sectional imaging on the diagnosis and prognosis of adrenocortical carcinoma: analysis of the National Cancer Database. Journal of Urology, 2011, 186, 805.
26. Reyes JM, Canter DJ, Sirohi M, Simhan J, Smaldone MC, Teper E, Kutikov A, Chen DY, Uzzo RG. Delayed proximal ureteric stricture formation after complex partial nephrectomy. BJU International. 2012, 109, 539.
27. Fogg R, Kutikov A, Uzzo RG, Canter D. How Hugh Hampton Young’s Treatment of President Woodrow Wilson’s Urinary Retention and Urosepsis Affected the Resolution of World War I. Journal of Urology, 2011, 186, 1153.
28. Lubbe W, Cohen R, Sharma N, Ruth K, Peters R, Li J, Buyyounouski M, Kutikov A, Chen DY, Uzzo RG, Horwitz E. Biochemical and clinical experience with real-time intraoperatively planned permanent prostate brachytherapy. Brachytherapy, Epub ahead of print, July 2011
29. Smaldone MC, Kutikov A, Egleston BL, Canter DJ, Viterbo R, Chen DY, Jewett MA, Greenberg RE, Uzzo RG. Small renal masses progressing to metastases under active surveillance: A systematic review and pooled analysis. Cancer, 2012, 118, 997.
30. Kutikov A, Piotrowski ZJ, Canter DJ, Li T, Chen DYT, Viterbo R, Greenberg RE, Boorjian SA, Uzzo RG. Routine Adrenalectomy is Unnecessary during Surgery for Large and/or Upper Pole Renal Tumors when the Adrenal is Radiographically Normal. Journal of Urology, 2011, 185, 1198.
31. Canter D, Simhan J, Smaldone MC, Lebed B, Tokar JL, Wu KN, Uzzo RG, Gustafson KS, Patchefsky AS, Plimack ER, Hoffman JP, Kutikov A. Clinical T1 Micropapillary Urothelial Carcinoma Presenting with Metastasis to the Pancreas. Urology, 2012, 79, e9.
32. Makhov P*, Kutikov A*, Golovine K, Uzzo RG, Canter DJ, Kolenko VM. Docetaxel-mediated apoptosis in myeloid progenitor TF-1 cells is mitigated by zinc: potential implication for prostate cancer therapy. Prostate, 2011, 71, 1413.
33. Mucksavage P, Kutikov A, Magerfleisch L, Van Arsdalen K, Wein AJ, Ramchandani P, Malkowicz SB. Comparison of radiographical imaging modalities for measuring the diameter of renal masses: is there a sizeable difference? BJU Int, 2011, 108, E232
34. Mucksavage P, Mitchell C, Kutikov A, Wein AJ, Torigian D, Malkowicz SB. Anthropometric differences in obese men with biochemical failure after radical retropubic prostatectomy. Urol Oncol, Epub ahead of print, March 2011
35. Canter D, Kutikov A, Sirohi M, Street R, Viterbo R, Chen DY, Greenberg RE, Uzzo RG. Prevalence of Baseline Chronic Kidney Disease in Patients Presenting With Solid Renal Tumors. Urology, 2011, 77, 781.
36. Kutikov A, Bonslaver J, Casey JT, Degrado J, Dusseault BN, Fox JA, Lashley-Rogers D, Richardson I, Smaldone MC, Steinberg PL, Trivedi DB, Routh JC. The Gatekeeper Disparity: Why Do Some Medical Schools Send More Medical Students into Urology? Journal of Urology, 2010, 185, 647.
37. Canter DJ, Viterbo R, Kutikov A, Wong YN, Plimack E, Zhu F, Oblaczynski M, Berberian R, Chen DY, Greenberg RE, Uzzo RG, Boorjian SA. Baseline Renal Function Status Limits Patient Eligibility to Receive Perioperative Chemotherapy for Invasive Bladder Cancer and Is Minimally Affected by Radical Cystectomy. Urology, 2011, 77, 160.
38. Canter DJ, Canter RJ, Kutikov A, Uzzo RG. Andrew Johnson’s rocky medical and political ‘calculous.’ BJU International, 2010, 106, 1569.
39. Golovine K, Makhov P, Uzzo RG, Kutikov A, Kaplan DJ, Fox E, Kolenko VM. Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-kappaB-independent, proteasome-mediated mechanism. Molecular Cancer, 2010, 9, 183.
40. Kutikov A, Egleston BL, Wong YN, Uzzo RG. Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. Journal of Clinical Oncology, 2010, 28, 311.
41. Piotrowski Z, Canter DJ, Kutikov A, Al-Saleem T, Pei J, Testa JR, Uzzo RG. Metanephric Adenofibroma: Robotic Partial Nephrectomy of a Large Wilms’ Tumor Variant. Can J Urol, 2010, 17, 5309.
42. Long C, Kutikov A, Canter DJ, Egleston BL, Chen DYT, Viterbo R, Boorjian SA, Uzzo RG. Percutaneous versus Surgical Cryoablation of the Small Renal Mass: Is Efficacy Compromised? BJU International, 2011, 107, 1376.
43. Canter DJ, Greenberg RE, Horwitz EM, Kutikov A, Li J, Long C, Buyyounouski M, Boorjian SA. Implantation of electromagnetic transponders following radical prostatectomy for delivery of IMRT. Can J Urol, 2010, 17, 5365.
44. Canter D, Long C, Kutikov A, Plimack E, Saad I, Oblaczynski M, Zhu F, Viterbo R, Chen DY, Uzzo RG, Greenberg RE, Boorjian SA. Clinicopathological outcomes after radical cystectomy for clinical T2 urothelial carcinoma: further evidence to support the use of neoadjuvant chemotherapy. BJU International, 2011, 107, 58.
45. Scoll BJ, Uzzo RG, Chen DYT, Boorjian SA, Kutikov A, Manley BJ, Viterbo R. Robot assisted partial nephrectomy: experience with 100 cases. Urology, 2010, 75, 1328.
46. Kutikov A, Uzzo RG. Renal Masses Herniating Into the Hilum: Technical Considerations of the "Ball-valve Phenomenon" During Nephron-sparing Surgery Reply. Urology. 2010, 75, 711.
47. Lebed B, Jani SD, Kutikov A, Iffrig K, Uzzo RG. Renal masses herniating into the hilum: Technical considerations of the “ball-valve phenomenon” during nephron sparing surgery. Urology, 2010, 75, 707. Cover article.
48. Kutikov A, Uzzo RG, Caraway A, Reese CT, Egleston BL, Chen DYT, Viterbo R, Greenberg RE, Wong YN, Raman JD, Boorjian SA. Utilization of Systemic Therapy and Factors Impacting Survival for Patients Undergoing Cytoreductive Nephrectomy. BJU International, 2010, 106, 218.
49. Kutikov A, Morgan TM, Resnick MJ. The impact of residency match information disseminated by a third-party website. Journal of Surgical Education, 2009, 66, 212.
50. Kutikov A, Uzzo RG. The R.E.N.A.L. Nephrometry Score: A comprehensive standardized scoring system for quantitating renal tumor size, location, and depth. Journal of Urology, 2009, 182, 844.
51. Mayer WA, Resnick MJ, Canter D, Ramchandani P, Kutikov A, Harryhill JF, Carpiniello VL, Guzzo TJ. Synchronous metastatic renal cell carcinoma to the genitourinary tract: two rare case reports and a review of the literature. Canadian Journal of Urology, 2009, 16, 4611.
52. Guzzo TJ, Kutikov A, Canter DJ, Tomaszewski JE, Magerfleish L, VanArsdalen K, Wein AJ, Malkowicz SB. The clinical and pathological history of prostate cancer progression in men with a prior history of high grade prostatic intraepithelial neoplasia. Canadian Journal of Urology, 2008, 15, 4174.
53. Kutikov A, Casale P, White MA, Mayer WA, Chang A, Gozalbez R, Canning DA. Testicular Compartment Syndrome: A New Approach to Conceptualizing and Managing Testicular Torsion. Urology, 2008, 72, 786. Cover article.
54. Kutikov, A, Van Arsdalen, KN, Gershman, B, Fossett, LK, Guzzo, TJ, Wein, AJ, Malkowicz, SB. Enucleation of renal cell carcinoma with ablation of tumor base. BJU International, 2008, 102, 688.
55. Kutikov, A, Van Arsdalen, KN, Levin, BM, Ferlise, VJ, Howard, PC, Carpenter, JP, Ramchandani P. Communication between the ureter and an aortic aneurysm sac following an abdominal aortic aneurysm repair. Urology, 2008, 71, 351.
56. Chang AY, Casale P, Kutikov A, Canning DA. A rare case of Gartner’s duct ectopic ureter. Dialogues in Pediatric Urology, 2008, 29, 7.
57. Kutikov A, Nguyen M, Guzzo TJ, Canter DJ, Casale P. Laparoscopic and robotic complex upper tract reconstruction in the child with a duplex collecting system. J. Endourology, 2007, 21, 621.
58. Kutikov A, Fossett LK, Ramchandani P, Tomaszewski JE, Siegelman ES, Banner MP, Van Arsdalen KN, Wein AJ, Malkowicz SB. Incidence of benign pathology at the time of partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on pre-operative imaging. Urology, 2006, 68, 737.
59. Kutikov A, Guzzo TJ, Canter DJ, Casale P. Initial experience with laparoscopic transvesical ureteral reimplantation at the Children’s Hospital of Philadelphia. J. Urol., 2006, 176, 2222
60. Kutikov A, Guzzo TJ, Canter DJ, Casale P. Robot assisted pyeloplasty in the infant – lessons learned. J. Urol. 2006, 176, 2237
61. Kutikov A, Resnick MJ, Casale P. Laparoscopic pyeloplasty in the infant less than 6 months of age: is it technically possible? J. Urol., 2006, 175, 1477; discussion 1479.
62. Barnes K, Kutikov A, Lippard SJ. Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes. Chemistry and Biology, 2004, 11, 557.
63. Moore S. J., Kutikov A, Lachicotte R. J., Marzilli, L. G. Methyl B12 models containing unsubstituted imidazole as an axial ligand investigated by structural and NMR spectroscopic methods. Evidence that μ-imidazolato-bridged dimers are formed by base addition to some analogues with macrocyclic equatorial ligands incorporating BF2. Inorganic Chemistry, 1999, 38, 768.

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Research Summary

My major interest is to setup the high throughput analysis of sequence data associated with cancer genome sequencing projects from the Institute for Personalized Medicine (IPM).  The first goal is to put together an analytical team and establish collaborations with other centers to stay up to date with quickly improving sequencing technology and to provide leading edge quantitative and computational methods for sequence analysis.

Selected Publications

1. Lykidis A, Pérez-Pantoja D, Ledger T, Mavromatis K, Anderson IJ, Ivanova NN, Hooper SD, Lapidus A, Lucas S, González B, Kyrpides NC. The complete multipartite genome sequence of Cupriavidus necator JMP134, a versatile pollutant degrader. PLoS One. 2010 Mar 22;5(3):e9729. Forthcoming 2010. PubMed
2. Wu D, Hugenholtz P, Mavromatis K, Pukall R, Dalin E, Ivanova NN, Kunin V, Goodwin L, Wu M, Tindall BJ, Hooper SD, Pati A, Lykidis A, Spring S, Anderson IJ, D'haeseleer P, Zemla A, Singer M, Lapidus A, Nolan M, Copeland A, Han C, Chen F, Cheng JF, Lucas S, Kerfeld C, Lang E, Gronow S, Chain P, Bruce D, Rubin EM, Kyrpides NC, Klenk HP, Eisen JA. A phylogeny-driven genomic encyclopaedia of Bacteria and Archaea. Nature. 2009 Dec 24;462(7276):1056-60. PubMed
3. Chain PS, Grafham DV, Fulton RS, Fitzgerald MG, Hostetler J, Muzny D, Ali J, Birren B, Bruce DC, Buhay C, Cole JR, Ding Y, Dugan S, Field D, Garrity GM, Gibbs R, Graves T, Han CS, Harrison SH, Highlander S, Hugenholtz P, Khouri HM, Kodira CD, Kolker E, Kyrpides NC, Lang D, Lapidus A, Malfatti SA, Markowitz V, Metha T, Nelson KE, Parkhill J, Pitluck S, Qin X, Read TD, Schmutz J, Sozhamannan S, Sterk P, Strausberg RL, Sutton G, Thomson NR, Tiedje JM, Weinstock G, Wollam A; Genomic Standards Consortium Human Microbiome Project Jumpstart Consortium, Detter JC. Genomics. Genome project standards in a new era of sequencing. Science. 2009 Oct 9;326(5950):236-7. PubMed
4. Lapidus, A. L. (2009) Genome Sequence Databases: Sequencing and Assembly. Encyclopedia of Microbiology. (Moselio Schaechter, Editor), pp. 196-210 Oxford: Elsevier.
5. Kunin V, Copeland A, Lapidus A, Mavromatis K, Hugenholtz P. A bioinformatician's guide to metagenomics. Microbiol Mol Biol Rev. 2008 Dec;72(4):557-78, Table of Contents. Review. PubMed
6. Chivian D, Brodie EL, Alm EJ, Culley DE, Dehal PS, DeSantis TZ, Gihring TM, Lapidus A, Lin LH, Lowry SR, Moser DP, Richardson PM, Southam G, Wanger G, Pratt LM, Andersen GL, Hazen TC, Brockman FJ, Arkin AP, Onstott TC. Environmental genomics reveals a single-species ecosystem deep within Earth. Science. 2008 Oct 10;322(5899):275-8. PubMed
7. Kalyuzhnaya MG, Lapidus A, Ivanova N, Copeland AC, McHardy AC, Szeto E, Salamov A, Grigoriev IV, Suciu D, Levine SR, Markowitz VM, Rigoutsos I, Tringe SG, Bruce DC, Richardson PM, Lidstrom ME, Chistoserdova L. High-resolution metagenomics targets specific functional types in complex microbial communities. Nat Biotechnol. 2008 Sep;26(9):1029-34. PubMed

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Improve Cancer Treatment by the Application of Cancer Genomics

The ultimate goal of our research is to improve cancer treatment by the application of cancer genomics. Current efforts focus on the structural genomic and functional genomic analyses of cancer to identify patient-specific alterations that are important for development, progression and treatment of cancer. Areas of research include: 1) systematic identification of genetic alterations in cancer patients by high-throughput sequencing, 2) investigation of oncogenic networks perturbed by these genetic alterations with high-throughput functional screens. By deepening our understanding of cancer genetics, this research will contribute to developing clinical trials with new therapies and matching emerging drug treatments to the unique genetics of individual patient tumors.

Selected Publications

1. Zhang Q, Gu J, Liu J, Luo B, Cheung HW, Boehm JS, Root DE, Polyak K, Brown M, Richardson A, Hahn WC, Kaelin WG, Bommi-Reddy A. Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell. 2009;16:413-24. PubMed
2. Luo B, Cheung HW, Subramanian A, Sharifnia T, Okamoto M, Yang X, Hinkle G, Boehm JS, Beroukhim R, Weir BA, Mermel C, Barbie D, Awad T, Zhou XC, Nguyen T, Piqani B, Li C, Golub T, Meyerson M, Hacohen N, Hahn WC, Lander ES, Sabatini DM, Root DE. Highly parallel identification of essential genes in cancer cells. Proc Natl Acad Sci U S A. 2008;105:20380-5. PubMed
3. Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G, Piqani B, Eisenhaure TM, Luo B, Grenier JK, Carpenter AE, Foo SY, Stewart SA, Stockwell BR, Hacohen N, Hahn WC, Lander ES, Sabatini DM, Root DE. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell. 2006;124:1283-98. PubMed
4. Luo B, Heard AD, Lodish HF. Small interfering RNA production by enzymatic engineering of DNA (SPEED). Proc Natl Acad Sci U S A. 2004;101:5494-9. PubMed
5. Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol Cell Biol. 1997;17:6057-67. PubMed
6. Aster J, Pear W, Hasserjian R, Erba H, Davi F, Luo B, Scott M, Baltimore D, Sklar J. Functional analysis of the TAN-1 gene, a human homologue of Drosophila notch. Cold Spring Harb Symp Quant Biol. 1994;59:125-36. PubMed

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Research Interests

Cutaneous melanoma has continued to increase in incidence.  It is an aggressive and often metastatic malignancy with limited responsiveness to available treatments.  Surgical removal of a suspect early lesion, together with a margin of surrounding skin, may currently be the only cure.  However, early lesions in human melanoma are often difficult to detect and may be phenotypically ambiguous.  A useful mouse model would therefore have the following features:  a standard-strain genetic background; early detectability of relevant skin lesions; occurrence of the major primary-tumor subtypes found in human cutaneous melanoma; propensity for widespread metastasis; and ease of accessibility for in vivo experimentation.  Our Tyr-SV40E (C57BL/6 strain) transgenic mouse models fulfill these requirements.  In the basic model, transgene DNA was injected into fertilized eggs and gave rise to a number of mouse lines, each with a distinctive level of transgene expression reflecting relative melanoma susceptibility.  Mice of high-expressing lines were expected to have high susceptibility but died young; low-susceptibility lines were long-lived but remained free of skin melanomas.  The problem was solved by grafting a small piece of skin from a high-susceptibility donor to a low-susceptibility host.  Malignant primary melanomas, comprising the two main subtypes, developed solely in the skin grafts and metastasized into organs of the hosts under the influence of factors involved in wound repair.  The tumors comprise the two major subtypes known in human melanoma, and they can metastasize widely.  In an additional model, not involving skin grafting, skin melanomas were induced by limited exposure of very young low-susceptibility transgenic mice to ultraviolet radiation.  In a still more recent model, with the same transgene conferring high-susceptibility, primary melanomas originated spontaneously at an early age in sites other than the skin.  The tumors were found to arise from multipotent neural crest stem cells arrested or diverted in migration.  Tumor cells were widely dispersed and were sometimes incorporated in developing organs.  The various models of experimentally induced or spontaneous melanomas are providing a rich source of material with which to clarify events underlying malignant melanoma promotion, progression, and metastasis.  We are also investigating the basis for tumor recurrence, in another mouse model in which apoptosis-resistant cells may generate melanomas.

Selected Publications

1. Mintz B, Silvers WK. "Intrinsic" immunological tolerance in allophenic mice (Reprinted from Science, vol 158, pg 1484-1487, 1967). J Immunol. 2007 Apr;178(7):4007-10.
2. Blelloch RH, Hochedlinger K, Yamada Y, Brennan C, Kim MJ, Mintz B, Chin L, Jaenisch R. Nuclear cloning of embryonal carcinoma cells. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):13985-90.
3. Milling SW, Sai T, Silvers WK, Mintz B. Inhibition of melanoma growth after treatment with dendritic cells in a Tyr-SV40E murine model requires CD4+ T cells but not CD8+ T cells. Melanoma Res. 2004 Dec;14(6):555-62.
4. Milling SW, Silvers WK, Sai T, Mintz B. Decline in MHC class I expression with increasing thickness of cutaneous melanomas in standard-strain transgenic mouse models. Melanoma Res. 2002 Jun;12(3):221-30.
5. Sai T, Milling SW, Mintz B. Freezing and thawing of bone marrow-derived murine dendritic cells with subsequent retention of immunophenotype and of antigen processing and presentation characteristics. J Immunol Methods. 2002 Jun 1;264(1-2):153-62.
6. Kelsall SR, Mintz B. Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility. Cancer Res. 1998 Sep 15;58(18):4061-5.
7. Orlow SJ, Silvers WK, Zhou BK, Mintz B. Comparative decreases in tyrosinase, TRP-1, TRP-2, and Pmel 17/silver antigenic proteins from melanotic to amelanotic stages of syngeneic mouse cutaneous melanomas and metastases. Cancer Res. 1998 Apr 1;58(7):1521-3.
8. Silvers WK, Mintz B. Differences in latency and inducibility of mouse skin melanomas depending on the age and anatomic site of the skin. Cancer Res. 1998 Feb 15;58(4):630-2.
9. Kelsall SR, LeFur N, Mintz B. Qualitative and quantitative catalog of tyrosinase alternative transcripts in normal murine skin melanocytes as a basis for detecting melanoma-specific changes. Biochem Biophys Res Commun. 1997 Jul 9;236(1):173-7.
10. Le Fur N, Kelsall SR, Silvers WK, Mintz B. Selective increase in specific alternative splice variants of tyrosinase in murine melanomas: a projected basis for immunotherapy. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5332-7.
11. Le Fur N, Silvers WK, Kelsall SR, Mintz B. Up-regulation of specific tyrosinase mRNAs in mouse melanomas with the c2j gene substituted for the wild-type tyrosinase allele: utilization in design of syngeneic immunotherapy models. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7561-5.
12. LeFur N, Kelsall SR, Mintz B. Base substitution at different alternative splice donor sites of the tyrosinase gene in murine albinism. Genomics. 1996 Oct 15;37(2):245-8.
13. Mintz B, Silvers WK. Accelerated growth of melanomas after specific immune destruction of tumor stroma in a mouse model. Cancer Res. 1996 Feb 1;56(3):463-6.
14. Devries TJ, Kitson JL, Silvers WK, Mintz B. Expression of Plasminogen Activators and Plasminogen-Activator Inhibitors in Cutaneous Melanomas of Transgenic Melanoma- Susceptible Mice. Cancer Res. 1995 Oct 15;55(20):4681-7.
15. Orlow SJ, Hearing VJ, Sakai C, Urabe K, Zhou BK, Silvers WK, Mintz B. Changes in Expression of Putative Antigens Encoded by Pigment Genes in Mouse Melanomas at Different Stages of Malignant Progression. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10152-6.
16. Kleinszanto AJ, Silvers WK, Mintz B. Ultraviolet Radiation-Induced Malignant Skin Melanoma in Melanoma-Susceptible Transgenic Mice. Cancer Res. 1994 Sep 1;54(17):4569-72.
17. Larue L, Dougherty N, Bradl M, Mintz B. Melanocyte Culture Lines from Tyr-Sv40e Transgenic Mice - Models for the Molecular Genetic Evolution of Malignant- Melanoma. Oncogene. 1993 Mar;8(3):523-31.
18. Mintz B, Silvers WK. Transgenic Mouse Model of Malignant Skin Melanoma. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8817-21.
19. Mintz B, Silvers WK, Kleinszanto AJ. Histopathogenesis of Malignant Skin Melanoma Induced in Genetically Susceptible Transgenic Mice. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8822-6.
20. Larue L, Dougherty N, Mintz B. Genetic Predisposition of Transgenic Mouse Melanocytes to Melanoma Results in Malignant-Melanoma after Exposure to a Low Ultraviolet-B Intensity Nontumorigenic for Normal Melanocytes. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9534-8.
21. Larue L, Dougherty N, Porter S, Mintz B. Spontaneous Malignant Transformation of Melanocytes Explanted from W(F)/W(F) Mice with a Kit Kinase-Domain Mutation. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7816-20.
22. Mintz B. Mosaic Expression of Mammalian Genes - Implications for Development and Neoplasia. Cytogenet Cell Genet. 1992;60(3-4):261.
23. Mintz B, Kleinszanto AJ. Malignancy of Eye Melanomas Originating in the Retinal-Pigment Epithelium of Transgenic Mice after Genetic Ablation of Choroidal Melanocytes. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11421-5.
24. Bradl M, Klein-Szanto A, Porter S, Mintz B. Malignant melanoma in transgenic mice. Proc Natl Acad Sci U S A. 1991;88(1):164-8.
25. Bradl M, Larue L, Mintz B. Clonal Coat Color Variation Due to a Transforming Gene Expressed in Melanocytes of Transgenic Mice. Proc Natl Acad Sci U S A. 1991 Aug;88(15):6447-51.
26. Kleinszanto A, Bradl M, Porter S, Mintz B. Melanosis and Associated Tumors in Transgenic Mice. Proc Natl Acad Sci U S A. 1991 Jan;88(1):169-73.
27. Mintz B, Bradl M. Mosaic Expression of a Tyrosinase Fusion Gene in Albino Mice Yields a Heritable Striped Coat Color Pattern in Transgenic Homozygotes. Proc Natl Acad Sci U S A. 1991 Nov;88(21):9643-7.
28. Porter S, Larue L, Mintz B. Mosaicism of Tyrosinase-Locus Transcription and Chromatin Structure in Dark Vs Light Melanocyte Clones of Homozygous Chinchilla-Mottled Mice. Dev Genet. 1991;12(6):393-402.
29. Porter S, Mintz B. Multiple Alternatively Spliced Transcripts of the Mouse Tyrosinase-Encoding Gene. Gene. 1991 Jan 15;97(2):277-82.
30. Capel B, Hawley RG, Mintz B. Long-Lived and Short-Lived Murine Hematopoietic Stem-Cell Clones Individually Identified with Retroviral Integration Markers. Blood. 1990 Jun 15;75(12):2267-70.
31. Larue L, Mintz B. Pigmented Cell-Lines of Mouse Albino Melanocytes Containing a Tyrosinase Cdna with an Inducible Promoter. Somat Cell Mol Genet. 1990 Jul;16(4):361-8.

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Overview of Research Interests

The promise of stem cell research is two-fold.  On one hand, stem cell replacement therapies may provide cures for diverse group of disorders, including cancer, diabetes, and traumatic injury.  On the other hand, the identification of cancer cells with self-renewing properties that promote tumor growth and evade conventional anti-cancer therapies may lead to the development of potent new approaches to cancer treatment.  Substantial progress has been made in the development of in vitro technologies that allow stem cells grow in culture and differentiate into specific cell types.  Far less progress has been made in identifying stem cells in situ and their mechanisms of regulation in functioning adult tissues. 

Our goal is to understand the mechanisms that control epithelial stem cell function in vivo.  Since identifying novel signals that regulate stem cell function is technically challenging in mammalian tissues, we are focusing on Drosophila ovarian Follicular epithelium Stem Cells (FSCs) as a model system for this analysis.  In this system, epithelial stem cells can be visualized directly in vivo.   Moreover, genetic mutational analysis allows us to pinpoint functional roles for specific genes in the cellular events required for stem cell commitment and self-renewal.  The striking conservation of stem cell control signals in mammals and flies suggests that novel stem cell regulatory mechanisms identified in the fly system will provide insight into epithelial stem cell control in normal mammalian tissue and in cancer.

Selected Publications

1. Hartman TM, Zinshteyn D, Schofield HK, Nicolas E, Okada A, O’Reilly AM. Drosophila Boi limits hedgehog levels to suppress follicle stem cell proliferation. J Cell Biol. 2010;191:943-952. PubMed
2. O’Reilly AM, Lee H-H, Simon MA. Integrins control the positioning and proliferation of Follicle Stem Cells in the Drosophila ovary. J Cell Biol. 2008;182(4):801-815. Featured article and subject of Biobytes podcast, August 25, 2008. PubMed
3. O’Reilly AM, Ballew AC, Miyazawa B, Stocker H, Hafen E, Simon MA. CSK differentially regulates Src64 during distinct morphological events in Drosophila germ cells. Development 2006;133:2627-2638. PubMed
4. O’Reilly AM, Pluskey S, Shoelson SE, Neel BG. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol Cell Biol. 2000;20:299-311. PubMed
5. O’Reilly AM, Neel BG. Structural determinants of SHP-2 function and specificity in Xenopus mesoderm induction. Mol Cell Biol. 1998;18:161-177. PubMed
6. Van Vactor D, O’Reilly AM, Neel BG. Genetic analysis of protein tyrosine phosphatases. Curr Opin Genet Dev. 1998;8:112-126. PubMed

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Rho GTPase Signaling in Cancer

Cancer and metastasis are associated with abnormal cellular signaling. Our goal is to understand how the Rho family of signaling proteins function in normal cells and how their signaling is altered in cancer and metastasis. In addition, we are applying novel high-throughput screening methods to identify drug-like molecules that target Rho signaling pathways. We use these compounds to study protein function in the laboratory and to validate new therapeutic approaches to cancer.

Selected Publications

1. Strochlic TI, Concilio S, Viaud J, Eberwine R, Wong LE, Minden A, Turk BE, Plomann M, Peterson JR. Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking. Proc Natl Acad Sci USA. 2012;109:4116-21. PubMed
2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011;29:1039-45. PubMed
3. Delorme-Walker VD, Peterson JR, Chernoff J, Waterman CM, Danuser G, DerMardirossian C, Bokoch GM Pak1 regulates focal adhesion strength, myosin IIA distribution and actin dynamics to optimize cell migration. J Cell Biol. 2011;193:1289-303. PubMed
4. Strochlic TI, Viaud J, Rennefahrt UEE et al. Phosphoinositides are essential co-activators for p21-activated kinase 1 (Pak1). Mol Cell. 2010;40(3):493-500. PubMed
5. Viaud J and Peterson J. An allosteric kinase inhibitor binds the p21-activated kinase (Pak) autoregulatory domain covalently. Mol Cancer Ther. 2009;8(9):2559-65. PubMed
6. Deacon SW, Beeser A, Fukui JA et al. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol. 2008;15(4):322-31. PubMed

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Mechanisms of Cell Fate Specification in Development and Cancer

Our lab is interested in the molecular mechanisms that control developmental cell fate decisions. Our current focus is on asymmetric cell division, a common strategy to achieve different cell fates during development. Dysregulation of asymmetric cell division in stem and progenitor cells likely contributes to a variety of human diseases, including cancer. In Drosophila, neural stem and progenitor cells divide asymmetrically and segregate a cell fate determinant, Numb, to one daughter cell during mitosis. Numb protein functions to inhibit the Notch signaling pathway. We currently use a combination of genetic, biochemical, molecular modeling, and live cell imaging approaches to study how cell fate determinants like Numb are polarized during mitosis, and how, following asymmetric cell division, Notch signaling is activated in one daughter cell and inhibited in the other daughter cell. Our studies have shown that the fly homologues of the human tumor suppressor genes tuberous sclerosis complex 1 and 2 (TSC1/2) and the novel transmembrane protein Sanpodo establish a specific context for Notch-mediated cell fate assignments in flies. As many of the genetic programs used in asymmetrically dividing cells are evolutionarily conserved, our studies will reveal fundamental mechanisms underlying control of cell fate in development.

Selected Publications

1. Tong X, Zitserman D, Serebriiskii I, Andrake M, Dunbrack R, Roegiers F. Numb independently antagonizes Sanpodo membrane targeting and Notch signaling in Drosophila sensory organ precursor cells. Mol Biol Cell. 2010 Mar 1;21(5):802-10. PubMed
2. Karbowniczek M, Zitserman D, Khabibullin D, Hartman T, Yu J, Morrison T, Nicolas E, Squillace R, Roegiers F*, Henske EP. The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. J Clin Invest. 2010 Jan 4;120(1):93-102. *Corresponding author PubMed
3. Roegiers F*, Kavaler J, Tolwinski N et al. Frequent unanticipated alleles of lethal giant larvae in Drosophila second chromosome stocks. Genetics. 2009;182(1):407-10. *Corresponding author PubMed
4. Roegiers F, Younger-Shepherd S, Jan LY et al. Two types of asymmetric divisions in the Drosophila sensory organ precursor cell lineage. Nat Cell Biol. 2001;3(1):58-67. PubMed
5. Lu B, Roegiers F, Jan LY et al. Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature. 2001;409(6819):522-5. PubMed

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Molecular Biology of Malignant Mesothelioma/AKT Function and Oncogenic Activity

Dr. Testa’s laboratory investigates the role of hereditary and somatic mutations in malignant mesothelioma, a cancer of the cells lining the chest and abdominal cavities, primarily caused by exposure to asbestos.  His group discovered frequent mutations of the CDKN2A/ARF locus, a region of DNA that encodes the tumor suppressors p16INK4a and p14ARF, and NF2 in human mesothelioma.  In 2011, he and his collaborators also discovered germline mutations of the BAP1 tumor suppressor gene in two families with a high incidence of mesothelioma, the first study demonstrating that inherited mutations can influence a person’s risk of mesothelioma.  Besides mesothelioma, some of the BAP1 mutation carriers developed ocular melanoma or other cancers, and this cancer susceptibility is now recognized as the BAP1 Syndrome.  Dr. Testa’s laboratory's current work on mesothelioma focuses on investigating the various molecular signaling pathways that are hyper-activated in this disease in order to identify novel druggable targets for cancer therapy or prevention.

The Testa laboratory also developed the first mouse model that faithfully reproduces many of the molecular features of human mesothelioma, which allows them to better understand mesothelioma tumor development and even test new therapies that could later be used in humans.  This mouse model is particularly useful since it demonstrates many characteristics common to the human form of the disease, including frequent inactivation of the Nf2 and Cdkn2a/Arf tumor suppressor genes, and hyper-activation of the enzyme Akt (AKT in humans), which plays a central role in the creation and progression of tumors.

Dr. Testa has a longstanding interest in the oncogenic role of AKT, beginning with his chromosomal mapping of the AKT1 proto-oncogene in 1988.  The Testa laboratory cloned and characterized the related AKT2 gene and provided the first evidence for recurrent alterations of the AKT pathway in human cancers.  We now know that genes encoding many components of this pathway, including PI3-kinase and PTEN, are repeatedly mutated in various cancers, leading to hyper-activation of AKT.  His group demonstrated that constitutive activation of Akt2 in the mouse thymus results in T-cell lymphomas characterized by chromosome inversion- or translocation-mediated activation of the Dlx5 and Myc oncogenes, respectively, which cooperate with Akt2 to promote oncogenesis.  The Testa laboratory also showed that the human homologue, DLX5, is overexpressed in human T-cell lymphomas and ovarian cancers, where it promotes tumor cell proliferation, in part by deregulating MYC.  His lab also discovered an AKT2 interactor dubbed APPL1, a novel adaptor now incriminated in multiple signaling pathways.

Selected Publications

1. Menges CW, Sementino E, Talarchek J, Xu J, Chernoff J, Peterson JR, Testa JR. Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways. Mol Cancer Res. 2012 Sep;10(9):1178-88. PubMed
2. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011 Aug 28;43(10):1022-5. doi: 10.1038/ng.912. PubMed
3. Altomare DA, Menges CW, Xu J, Pei J, Zhang L, Tadevosyan A, Neumann-Domer E, Liu Z, Carbone M, Chudoba I, Klein-Szanto AJ, Testa JR. Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLoS One. 2011 Apr 19;6(4):e18828. PubMed
4. Tan Y, Cheung M, Pei J, Menges CW, Godwin AK, Testa JR. Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS2-AKT Signaling. Cancer Res. 2010 Nov 15;70(22):9197-206. PubMed
5. Altomare DA, Zhang L, Deng J, Di Cristofano A, Klein-Szanto AJ, Kumar R, Testa JR. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res. 2010 Jan 15;16(2):486-96. [article featured in journal Highlights section]. PubMed
6. Xu J, Testa JR. DLX5 (Distal-less homeobox 5), promotes tumor cell proliferation by transcriptionally regulating MYC. J Biol Chem. 2009 Jul 31;284(31):20593-601. PubMed
7. Altomare DA, Menges CW, Pei J, Zhang L, Skele-Stump KL, Carbone M, Kane AB, Testa JR. Activated TNFa/NFkB signaling via down regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3420-5. PubMed

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Research Interests

The cell content of organisms changes throughout their lifetimes, cells become physically damaged, accumulate mutations resulting in cell death or relocate within the organism. In order to preserve proper organ function, tissues need to replace these lost cells by generating new ones. This is accomplished by populations of adult stem cells which undergo divisions in response to the decreasing cell supply within a tissue. Rates of stem cell divisions vary from one tissue to another, dependent on factors specific to the tissue as well as regulators that simultaneously affect multiple organs or the organism as a whole.   Our laboratory is interested in studying molecular mechanisms that regulate mitotic activity of adult stem cells, using the fruit fly, Drosophila melanogaster, as the model system for our research. In particular, we focus on assessing how wakefulness, sleep, stress and disease may modulate stem cell division.

Selected Publications

1. Issigonis M, Tulina N, de Cuevas M, Brawley C, Sandler L, Matunis E. JAK-STAT signal inhibition regulates competition in the Drosophila testis stem cell niche. Science. 2009 Oct 2;326(5949):153-6. PubMed
2. Terry NA, Tulina N, Matunis E and DiNardo S. Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev Biol. 2006 Jun 1;294(1):246-57. Epub 2006 Apr 17. PubMed
3. Tulina N.M. Molecular control of spermatogonial stem cell self-renewal by glycoprotein Unpaired, a cytokine homolog, in Drosophila melanogaster. Dokl Biol Sci. 2003 Jan-Feb;388:79-82. PubMed
4. Tulina NM and Matunis EL. Jak-Stat signaling maintains germline and somatic stem cell fate during Drosophila spermatogenesis. Science. v.2001;294:2546-2549.

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Role of Poly(ADP-ribose)Polymerase in Chromatin Programming and Transcription

Developmentally regulated gene expression in multicellular eukaryotes requires the formation of dynamic tissue-specific chromatin structures that participate in activating certain genes and silencing others (Wolffe, Essays Biochem. 37:45, 2001). Furthermore, during an organism’s lifetime the established pattern of chromatin needs to be quickly reprogrammed in a response to environmental or hormonal signals (Thummel, Insect Biochem. Mol. Biol. 32:113, 2002). It has become increasingly clear that key aspects of chromatin structure and gene transcriptional activity are determined by a specific modification of histones (Elgin and Workman, Curr Opin Genet Dev. 12: 127, 2002; Fischle et al., Nature. 425:475, 2003).

Despite this exciting progress there remains much to be learned about how chromatin is programmed and how active or inactive domains are maintained. Our studies of the abundant nuclear enzyme poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) demonstrated that it plays novel and previously unknown roles in many of these processes. Distributed evenly along chromatin PARP is responsible for rapid local chromatin decondensation (loosening), which is required for transcriptional activation of many genes within particular chromatin blocks. Previously we have demonstrated that poly(ADP-ribosyl)ation is also involved in heterochromatin formation, the initiation and maintenance of nucleoli and telomere metabolism. The presence of several PARP-related proteins in mammals complicates the analysis and interpretation of results. Fortunately, only a single PARP gene is present in the Drosophila genome, making this animal an invaluable model system to study PARP function. Using Drosophila we study the molecular mechanisms of PARP activation, its action on chromatin and the interaction of PARP with other components of the chromatin remodeling machinery and transcriptional apparatus.

Selected Publications

1. Ji Y, Tulin AV. Poly(ADP-ribose) controls DE-cadherin-dependent stem cell maintenance and oocyte localization. Nat Commun. 2012 Mar 27;3:760. doi: 10.1038/ncomms1759. PubMed
2. Boamah EK, Kotova E, Garabedian M, Jarnik M, Tulin AV. 2012. Poly(ADP-ribose) Polymerase 1 (PARP-1) regulates ribosomal biogenesis in Drosophila nucleoli. PLoS Genetics. 8(1):e1002442.
3. Tulin A. Re-evaluating PARP1 inhibitor in cancer. Nat Biotechnol. 2011. 29(12):1078-9. PubMed
4. Kotova E, Lodhi N, Jarnik M, Pinnola AD, Ji Y, Tulin AV. Drosophila histone H2A variant (H2Av) controls Poly(ADP-Ribose) Polymerase 1 (PARP1) activation in chromatin. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6205-10. PubMed
5. Kotova E, Jarnik M, Tulin AV. Uncoupling of the trans-activation and trans-repression functions of PARP1 protein. Proc Natl Acad Sci U S A. 2010;107(14):6406-11. PubMed
6. Ji Y, Tulin AV. Poly(ADP-ribosyl)ation of Heterogeneous Nuclear Ribonucleoproteins Modulates Splicing. Nucl. Acids Research. 2009;37:3501-13. PubMed
7. Kotova E, Jarnik M, Tulin AV. Poly (ADP-ribose) Polymerase 1 is required for protein localization to Cajal body. PLoS Genetics. 2009;5(2):e1000387. PubMed
8. Pinnola AD, Naumova N, Shah M, Tulin AV. Nucleosomal core histones mediate dynamic regulation of PARP1 protein binding to chromatin and induction of PARP1 enzymatic activity. J Biol Chem. 2007;282:32511-9. PubMed
9. Tulin A, Naumova N, Menon A, Spradling A. The Drosophila Poly(ADP-ribose) Glycohydrolase (Parg) protein mediates chromatin structure and Sir2-dependent silencing. Genetics. 2006;172:363-371. PubMed
10. Tulin A, Chinenov Y, Spradling A. Regulation of chromatin structure and gene activity by Poly(ADP-ribose) polymerases. Curr Top Devel Biol. 2003;56:55-83. PubMed
11. Tulin A, Spradling A. Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science. 2003;299(5606):560-2. PubMed
12. Tulin A, Stewart D, Spradling AC. The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 2002;16(16):2108-19. PubMed

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Research Interests

Our research efforts span the basic and the clinical sciences. Our work focuses on understanding the process of renal and prostatic carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers.

As part of our work, we explore the role of zinc in development and progression of prostate malignancy.  Zinc concentrations diminish early in the course of prostate carcinogenesis -- prior to histopathological changes -- and continue to decline during progression toward castration-resistant growth.  The objective of research in our laboratory is to test and advance an emerging paradigm that intracellular zinc deficiency augments malignant potential of prostate cancer cells and, therefore, promotes prostate tumorigenesis. We are also investigating the role of zinc chelators as potential therapeutic agents for the treatment of castration-resistant prostate cancer. Work performed by Dr. Kolenko indicates that treatment of prostate cancer cells with the zinc chelating agent TPEN induces selective down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and sensitizes cancer cells to cytotoxic agents.  Importantly, the observed effect is not limited to prostate cancer, as TPEN reduces expression of XIAP in malignant cell lines of various origins e.g. colon, ovarian, leukemia, breast and cervical.

The second major theme of our research is to determine the mechanism of tyrosine kinase inhibitor (TKIs)-resistance in genitourinary tumors. Our studies reveal that TKI-resistance coincides with the loss of phosphatase and tensin homolog (PTEN) protein expression in prostate and renal malignant cells. On the contrary, expression of PTEN sensitizes prostate and renal tumors to multi-targeted tyrosine kinase inhibitor sunitinib both in vitro and in vivo. In addition, our studies indicate that an increase in expression of IL-6 and IL-8 correlates with sunitinib and pazopanib resistance in prostate and renal tumor cells.  Use of a reliable biomarker for TKI response, harbors promise both in the clinical and in the research settings.

In the clinical arena, we focus our efforts on addressing quantification of competing risks of death for patients with urologic malignancies, investigating the biology and natural history of small renal masses, improving reporting and risk-stratification of surgical outcomes for patients with kidney cancer, and addressing clinical approaches to patients with adrenal cancers and incidental adrenal masses.   

Selected Publications

1. Kutikov A, Piotrowski ZJ, Canter DJ, Li T, Chen DYT, Viterbo R, Greenberg RE, Boorjian SA, Uzzo RG. Routine Adrenalectomy is Unnecessary during Surgery for Large and/or Upper Pole Renal Tumor when the Adrenal is Radiographically Normal. Journal of Urology, in press.
2. Golovine K, Makhov P, Uzzo RG, Kutikov A, Kaplan DJ, Fox E, Kolenko V: Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-κB-independent, proteasome-mediated mechanism. Molecular Cancer 9(1):183, 2010.
3. Lane BR, Russo P, Uzzo RG, Hernandez AV, Boorjian SA, Thompson RH, Fergany AF, Love TE, Campbell SC: Comparison of warm and cold ischemia during open partial nephrectomy for tumor in a solitary kidney. J Urol, (submitted), 2010.
4. Gupta V, Simons JD, Bassi DE, Al-Saleem TI, Uzzo RG, Cukierman E: Fibroblast-derived 3-D matrix system mimics in vivo stromal changes during renal cell carcinoma progression. J Am Soc Nephrol, (submitted), 2010.
5. Canter D, Kutikov A, Uzzo RG, Greenberg RE, Viterbo R, Fang Z, Chen DYT, Wong YN, Plimack E: Baseline renal function status limits patient eligibility to receive perioperative chemotherapy for invasive bladder cancer and is minimally impacted by radical cystectomy. Urology, [E-pub ahead of print], 2010.
6. Piotrowski Z, Canter DJ, Kutikov A, Al-Saleem T, Testa J, Uzzo RG: The Metanephric Adenofibroma: Robotic partial nephrectomy of a Large Benign Wilms’ Tumor Variant. Canadian J Urol, 17:5309, 2010.
7. Boorjian SA, Uzzo RG: The case for active surveillance of the small renal mass. J Urol, (in press), 2010.
8. Giri, VN, Ruth, K, Hughes, L, Uzzo, RG, Chen, DYT, Boorjian, SA, Viterbo, R, and Rebbeck, TR. Racial differences in prediction of time to prostate cancer diagnosis in a prospective screening cohort of high-risk men: Effect of TMPRSS2 Met160Val. BJU Intl,[E-pub ahead of print], 2010.
9. Long CJ, Kutikov A, Canter DJ, Egleston, Chen DYT, Viterbo R, Boorjian SA, Uzzo RG: Percutaneous versus Surgical Cryoablation of the Small Renal Mass: Is Efficacy Compromised? BJU Intl, (in press), 2010.
10. Canter D, Long C, Kutikov A, Plimack E, Zhu F, Viterbo R, Chen DYT, Uzzo RG, Greenberg RE, Boorjian SA: Clinicopathological Outcomes after Radical Cystectomy for Patients with Clinical T2 Urothelial Carcinoma: Further Evidence to Support the Use of Neoadjuvant Chemotherapy, BJU Intl,[E-pub ahead of print], 2010.
11. Aron M, Gill IS, Boorjian SA, Uzzo RG: Treatment of the 2 to 3cm Renal Mass. J Urol, [E-pub ahead of print], 2010
12. Brien JC, Shariat SF, Herman MP, Ng CK, Scherr DS, Scoll B, Uzzo RG, Wille M, Eggener SE, Terrell JD, Lucas SM, Lotan Y, Boorjian SA, Raman JD: Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper-tract urothelial carcinoma. J Urol, 184 (1):69-73, 2010.
13. Campbell SC, Derweesh IH, Faraday MM, Uzzo RG: re: Gill, et al: Small Renal Mass. N Engl J Med, 362; 24:2334-5, 2010.
14. Campbell SC, Faraday M, Uzzo RG, Gill IS, Aron M, Jewett MAS: Small Renal Mass. N Engl J Med, 362; 24:2334-5, 2010.
15. Pei J, Feder MM, Al-Saleem T, Liu Z, Liu A, Hudes GR, Uzzo RG, Testa JR: Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma. Genes Chromosomes Cancer, 49(7):610-9, 2010.
16. Kutikov A, Egleston BL, Wong YN, Uzzo RG: Reply to J. Lagro et al and G. Lughezzani et al, J Clin Oncol, 28:e301, 2010.
17. Sharma NK, Eade TN, Buyounouski MK, Jinsheng L, McNeeley S, Crawford K, Chen DYT, Uzzo RG, Horwitz EM: An Intra-Operative real-time sleeved seed technique for permanent prostate brachytherapy. Brachytherapy, 9(2):126-30, 2010.
18. Lebed B, Jani SD, Kutikov A, Iffrig K, Uzzo RG: Renal Masses Herniating into the Hilum: Technical Considerations of the "Ball-Valve Phenomenon" During Nephron Sparing Surgery. Urology, 75(3):707-10, 2010. (cover featured article)
19. Toujer K, Jacqmin D, Kavoussi LR, Montorsi F, Patard JJ, Rogers CG, Russo P, Uzzo RG, Van Poppel H: The expanding Role of Partial Nephrectomy: A Critical Analysis of Indications, Results, and Complications. Eur Urol, 57 (2):214-22, 2010.
20. Kutikov A, Egleston BL, Wong YN, Uzzo RG: Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Onc, 28(2):311-7, 2010.
21. Kutikov A, Uzzo RG: Moving Forward: Objectifying Criteria for Partial Nephrectomy (editorial). Urology, (75): 3, 711-12, 2010.
22. Scoll BJ, Uzzo RG, Chen DYT, Boorjian SA, Kutikov A, Manley BJ, Viterbo R: Robot Assisted Partial Nephrectomy: A large single institutional experience, Urology, 75(6):1328-34, 2010.
23. Lipton A, Uzzo RG, Amato RJ, Ellis GK, Hakimian B, Roodman GD, Smith MR: The Science and Practice of Bone Health in Oncology: Managing Bone Loss and Metastasis in Patients with Solid Tumors. J Natl Compr Canc Netw, 7; S1-S29, 2009.
24. Kutikov A, Uzzo RG, Caraway A, Reese CT, Egleston BL, Chen DYT, Viterbo R, Greenberg RE, Wong YN, Raman JD, Boorjian SA: Use of systemic therapy and factors affecting survival for patients undergoing cytoreductive nephrectomy. BJU Int, [E-pub ahead of print], 2009.
25. Uzzo RG: Editorial Comment: Laparoscopy and Robotics. Urology, 74(5), November, 2009.
26. Campbell SC, Novick AC, Belldegrun A, Blute ML, Chow GK, Derweesh IH, Faraday MM, Kaouk JH, Leveillee RJ, Matin S, Russo P, Uzzo RG: Guideline for Management of the Clinical T1 Renal Mass. J Urol, 182(4):1271-9, 2009.
27. Kunkle DA, Kutikov A, and Uzzo RG: Management of small renal masses. Semin Ultrasound CT MR, 30(4): 352-8, 2009.
28. Chen DY, Uzzo RG: Optimal management of localized renal cell carcinoma: surgery, ablation, or active surveillance. J Natl Compr Canc Netw, 7: 635, 2009.
29. Kutikov A, Uzzo RG. The RENAL Nephrometry Score: A Comprehensive Standardized System for Quantitating Renal Tumor Size, Location and Depth. J Urol, 182(3):844-53, 2009.
30. Uzzo RG: Laparoscopic Partial Nephrectomy in Octogenarians – Can a “Small” Knife extend a “Long” Life? Urology 74(5), 1044-5, 2009.
31. Wong YN, Freedland SJ, Egleston B, Vapiwala N, Uzzo RG, Armstrong K: The role of primary androgen deprivation therapy in localized prostate cancer. Eur Urol, 56(4):609-16, 2009.
32. Scoll B, Crispen P, Wong YN, Egleston B, Saad I, Uzzo RG: Age, tumor size, and relative survival in localized renal cell carcinoma: a surveillance, epidemiology and end results analysis. J Urol, 181 (2): 506-11, 2009.
33. Rothman J, Egleston B, Wong YN, Iffrig K, Lebovitch S, Uzzo RG: Histopathologic characteristics of localized renal cell carcinoma correlate with tumor size: a SEER analysis, J Urol, 181 (1): 29-34, 2009.
34. Kunkle DA, Uzzo RG, Cadeddu JA. Cryoablation or Radiofrequency Ablation of the Small Renal Mass: A Meta-Analysis Editorial Comment. J Urol, 181(4):1601-2, 2009.
35. Boorjian SA, Uzzo RG: The evolving management of small renal masses. Curr Oncol Rep, 11(3):211-7, 2009.
36. Giri V, Egleston B, Ruth K, Uzzo RG, Chen DYT, Buyyounouski M, Raysor S, Hooker S, Torres J, Ramike T, Mastalski K, Kim T, Kittles R: Race, Genetic West African Ancestry, and Prostate Cancer Prediction by PSA in Prospectively Screened High-Risk Men. Cancer Prev Res, (2): 244-250, 2009.
37. Crispen PL, Boorjian SA, Viterbo R, Chen DYT, Uzzo RG: Natural History, Growth Kinetics and Outcomes of Untreated Clinically Localized Renal Tumors Under Active Surveillance, Cancer, 115 (13): 2844-52, 2009.
38. Cooperberg MR, Hinotsu S, Chancellor MB, Homma Y, Nelson PS, Matsuyama H, Menon M, Kucuk O, Hara I, Egawa S, Uzzo RG, Kanayama HO, Okuyama A, Akaza H: Fourth joint meeting of the American Urological Association and the Japanese Urological Association Specialty Society program at the 104th annual meeting of the American Urological Association at Chicago 2009. Int J Urol, 16(8): 703-8, 2009.
39. Kutikov A, Kunkle D, Uzzo RG: Focal therapy for kidney cancer: a systematic review. Current Opinions in Urology, 19 (2): 148-53, 2008.
40. Makhov P, Golovine K, Uzzo RG, Wuestefeld T, Scoll BJ, Kolenko VM: Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells. Gene, 431(1-2):39-46, 2008.
41. Uzzo RG, Rohde D. Results of the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs) evaluating sorafenib in metastatic clear cell kidney cancer – implications for the urologist. Urol Onc, (submitted), 2008.
42. Golovine K, Makhov P, Uzzo RG, Shaw T, Kunkle D, Kolenko VM: Overexpression of the zinc uptake transporter hZIP1 inhibits NF-κB and reduces the malignant potential of prostate cancer cells in vitro and in vivo. Clin Cancer Res, 14: 5376-84, 2008.
43. Makhov P, Golovine K, Uzzo RG, Rothman J, Crispen PL, Shaw T, Scoll BJ: Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Cell Death Differ, 15(11):1745-51, 2008.
44. Crispen PC, Wong YN, Greenberg RE, Chen DYT, Uzzo RG: Predicting growth of solid renal masses under active surveillance. Urol Oncol, 26: 555-9, 2008.
45. Kunkle DA, Egleston BL, Uzzo RG: Cryoablation vs. radiofrequency ablation of the small renal mass: A meta-analysis of published literature. Cancer, 113(10):2671-2680, 2008.
46. Golovine K, Uzzo RG, Makhov P, Crispen PLP, Shaw T, Kunkle D, Kolenko VM: Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kappaB- dependent pathway. Prostate, 68: 1443-9, 2008.
47. Uzzo, RG: Renal Masses: To treat or not to treat – if that is the question are contemporary biomarkers the answer? J Urol, 180 (2): 433-4, 2008.
48. Haas NB, Uzzo RG: Adjuvant therapy for renal cell carcinoma. Current Oncol Rep, 10(3):245-52, 2008.
49. Kunkle DA, Egelston B, Uzzo RG: Re: Excise, ablate or observe the small renal mass: Moving away from “it works” toward critical assessments with meaningful oncologic endpoints. J Urol, 180 (4): 1568, 2008.
50. Rothman J, Crispen PL, Wong YN, Al-Saleem T, Fox EB, Uzzo RG: Pathologic concordance of sporadic synchronous bilateral masses. Urology, (72) 1: 138-42, 2008.
51. Kaplan DJ, Crispen PL, Greenberg RE, Chen DYT, Viterbo R, Buyyounouski MK, Horwitz EM, Uzzo RG: Residual prostate cancer after radiotherapy: a study of radical cystoprostatectomy specimens. Urology, 72 (3): 654-8, 2008.
52. D'Ambrosio DJ, Ruth K, Horwitz, EM, Uzzo RG, Pollack A, Buyyounouski MK: How can men destined for biochemical failure after androgen deprivation and radiotherapy be identified earlier? Int. J Rad Onc Bio Phys, 70 (5): 1487-91, 2008.
53. Abramowitz MC, Li TN, Buyyounouski MK, Ross E, Uzzo RG, Pollack A and Horwitz EM. The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer; 112 (1): 55-60, 2008.
54. Uzzo RG, Haas NB, Crispen PL, Kolenko V: Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone refractory prostate cancer. Cancer, 112 (8): 1660-71, 2008.
55. Uzzo RG: Is CT-guided percutaneous radiofrequency ablation oncologically effective in patients with renal cell carcinoma? Nat Clin Prac Urol, 1 (5): 18-9, 2008.
56. Kunkle DA, Egleston BL, Uzzo RG: Excise, ablate or observe: the small renal mass dilemma – a meta-analysis and review. J Urol, 179 (4):1227-33, discussion 1233-4, 2008.
57. Crispen PL, Viterbo R, Fox EB, Greenberg RE, Chen DYT, Uzzo RG: Delayed intervention of small sporadic renal masses undergoing active surveillance. Cancer, 112 (5):1051-57, 2008.
58. Cairns, P, Uzzo, RG: Methylation-based detection of kidney cancer. Cancer Biomarkers 4:136-137, 2008.
59. Haas NB, Kunkle DA, Uzzo RG: Adjuvant therapy for high risk renal carcinoma patients. Current Oncol Rep, 8 (1): 19, 2007.
60. Crispen PL, Greenberg RE, Chen DY, Uzzo RG: Observation of small renal masses. Russian Journal of Urology 4: 17-21, 2007.
61. Haas NB, Uzzo RG: Tyrosine kinase inhibitors and anti-angiogenic therapies in kidney cancer. Curr Treat Options Oncol 8(3): 211-26, 2007.
62. Haas NB, Uzzo RG: Targeted therapies for kidney cancer in urologic practice. Urologic Oncology: 25 (5): 420-32, 2007.
63. Giri V, Beebe-Dimmer J; Buyyounouski M, Konski A, Feigenberg SJ , Uzzo RG, Hanks G, Godwin A, Chen DYT, Gordon R, Cescon T, Raysor R; Watkins Bruner D: Prostate cancer risk assessment program – a ten-year update of cancer detection. J Urol 178 (5): 1920-24, 2007.
64. Haas NB, Uzzo RG: ECOG 2805: A Randomized, double blind phase III trial of adjuvant Sunitinib versus Sorafenib versus placebo in patients with resected renal cell carcinoma. US Genitourinary Disease (2), 2006.
65. Kunkle DA, Haas NB, Uzzo RG: Adjuvant strategies for high risk renal cell carcinoma patients. Current Urology Reports, 8 (1): 19-30, 2007.
66. Morgan PB, Hanlon AL, Horwitz EM, Buyyounouski MK, Uzzo RG, Pollack A: Radiation dose and late failures in prostate cancer. Int. J Rad Onc Bio Phys 67 (4): 1074-81, 2007.
67. Morgan PB, Hanlon AL, Horwitz EM, Buyyounouski MK, Uzzo RG, Pollack A: Timing of biochemical failure and distant metastases for low, intermediate and high risk prostate cancer after radiotherapy. Cancer 110 (1): 68-80, 2007.
68. Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG: Enhancing renal masses with zero net growth during active surveillance. J Urol 177 (3): 849-54, 2007.
69. Kunkle DA, Cripsen PL, Uzzo RG: Tumor size predicts synchronous metastases in renal cell carcinoma: Implications for surveillance of small renal masses. J Urol 177 (5): 1692-96, 2007.
70. Crispen PL, Uzzo RG: The natural history of untreated renal masses. Brit J Urol 99 (5): 1203-07, 2007.
71. Crispen PL, Uzzo RG: Renal cell carcinoma: can some be observed? Contemporary Urology 19 (5): 10-17, 2007.
72. D'Ambrosio DJ, Hanlon AL, Feigenberg, SJ,Horwitz EM, Uzzo RG, Pollack A, Buyyounouski MK: The proportion of prostate biopsy tissue with Gleason pattern 4 or 5 predicts for biochemical and clinical outcome after radiotherapy for prostate cancer. Int. J Rad Onc Bio Phys. 67 (4): 1082-87, 2007.
73. Crispen PL, Uzzo RG, Golovine K, Makhov P, Pollack A, Horwitz EM, Greenberg RE, Kolenko VM: Vitamin E Succinate inhibits NF-κB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate 67 (6): 582-90, 2007.
74. Dulaimi E, Uzzo RG, Ibanez de Caceres I, Greenberg RE, Al-Saleem T, Cairns P: Monitoring of tumor suppressor gene methylation in urine from follow-up renal cancer patients. Nat Rev Cancer, 7 (7):531-543, 2007.
75. Ibanez de Caceres, I, Dulaimi, E, Hoffman, AM, Al-Saleem, T, Uzzo, RG, Cairns, P: Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Research, 66 (10); 5021, 2006.
76. Uzzo RG, Crispen PL, Golovine K, Makhov P, Horwitz EM, Kolenko V: Diverse effects of zinc on transcriptional control of NF-kB and AP-1:implications for prostate cancer progression Carcinogenesis 27 (10): 1980-90, 2006.
77. Halbert RJ, Figlin RA, Atkin MB, Bernal M, Hutson TE, Uzzo RG, Bukowski RM, Khan KD, Wood CG, Dubois R: Treatments for patients with metastatic renal cell cancer: A Rand Appropriateness Panel. Cancer. 107 (10): 2375-83, 2006.
78. Matin SF, Ahrar K, Cadeddu JA, Gervais DA, McGovern FJ, Zagoria RA, Uzzo RG, Haaga J, Resnick MI, Kaouk J, Gill IS: Residual and recurrent disease following renal energy ablative therapy: implications for management – a multi-institutional study. J Urol 176 (5): 1973-77, 2006.
79. Pollack A, Hanlon AL, Horwitz EM, Feigenberg SJ, Konski AA, Movsas B, Greenberg RE, Uzzo RG, Ma CM, McNeeley SW, Buyyounouski M, Price RA: Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial. Int. J Rad Onc Bio Phys. 64 (2): 518-26, 2006.
80. Chawla S, Crispen P, Hanlon A, Greenberg RE, Chen D, Uzzo RG: The natural history of enhancing renal masses: A meta-analysis and review of the world literature. J Urol. 175 (2): 425-31, 2006.
81. Feigenberg SJ, Hanlon A, Horwitz E, Uzzo RG, Eisenberg D, Pollack A: A PSA bounce of greater than 1.4 ng/ml is clinically significant following external beam radiotherapy for prostate cancer. Amer J Clin Oncol. 29 (5): 458-62, 2006.
82. Feigenberg SJ, Hanlon AL, Horwitz EM; Uzzo RG; Pollack A.: Long term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three dimensional conformal radiation therapy, J Rad Onc Bio Phys. 62 (2): 397-405, 2005.
83. Uzzo RG: Renal Cell Carcinoma: Urologists in a New Era J Urol. 174: 1723, 2005.
84. Uzzo RG: Does pathological stage affect the prognosis for patients with clinically staged T1 renal cell carcinoma? Nature Clinical Practice Urology 2 (5): 211-213, 2005.
85. Watkins Bruner D., Linton S., Konski A., Uzzo RG, Greenberg RE, Pollack A, Gordon R., Cescon TP, Daly M, Young W., Goplerud J, Higman-Tofani S, Engstrom P: Successful strategies for African American recruitment to prostate cancer research. Int J Canc Prev 1(4): 295-306, 2005.
86. Buyyounouski MK, Hanlon AL, Eisenberg DF, Horwitz EM, Feigenberg SJ, Uzzo RG, Pollack A: Defining biochemical failure following radiation therapy with and without androgen deprivation for prostate cancer. Int. J Rad Onc Bio Phys.63:5, 1455, 2005.
87. Jacob R, Hanlon AL, Horwitz EM, Movsas B, Uzzo RG, Pollack A: Role of prostate dose escalation in patients with > 15% risk of pelvic lymph node involvement. Int J. Radiation Oncology Biol Phys, 61 (3); 695-701, 2005.
88. Andrews SF, Horwitz EM, Feigenberg SJ, Eisenberg DF, Hanlon AL, Uzzo RG, Pollack A: Does a delay in initiation of external beam radiation therapy after tissue diagnosis effect outcome for men with prostate cancer? Cancer 104 (2): 299-304, 2005.
89. Yamaguchi K, Uzzo RG, Pimkina J, Golovine K, Makhov P, Kolenko VM: Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Oncogene 24: 5868, 2005.
90. Viterbo R, Greenberg RE, Al-Saleem T, Uzzo RG: Prior abdominal surgery and radiation do not complicate the retroperitoneoscopic approach to the kidney or adrenal gland. J Urol. 174 (2): 446-450, 2005.
91. Buyyounouski MK, Hanlon AL, Horwitz EM, Uzzo RG, Pollack A.: Biochemical failure and the temporal kinetics of prostate specific antigen following radiation therapy with androgen deprivation. J Rad Onc Bio Phys. 61(5): 1291-1298, 2005.
92. Feigenberg SJ; Hanlon AL, Horwitz EM, Uzzo RG, Eisenberg D, Pollack A: What pretreatment PSA warrants long term androgen deprivation? J Rad Onc Bio Phys. 61 (4): 1003-10, 2005.
93. Jacob R, Hanlon AL, Horwitz EM, Movsas B, Uzzo RG, Pollack A: Role of prostate dose escalation in patients with greater than 15% risk of pelvic lymph node involvement. Int. J Rad Onc Bio Phys. 61 (3):695-701, 2005.
94. Manne, SL, Ostroff, JS, Winkel, G, Fox, K, Grana, G, Miller, E, Ross, S, Frazier, T, Buyyounouski, MK, Hanlon, AL, Eisenberg, DF, Horwitz, EM, Feigenberg, SJ, Uzzo, RG, Pollack, A, Morrow, M, Chen, JQ, Yager, JD, Russo, J, Bassi, DE, Fu, J, Lopez de Cicco, R, Klein-Szanto, AJ, Devlin, J, Sherman, E, Altomare, DA, Vaslet, CA, Skele, KL, De Rienzo, A, Devarajan, K, Jhanwar, SC, McClatchey, AI, Kane, AB, Testa, JR, Murphy, ME, Langer, CJ, Mehta, MP, Viterbo, R, Greenberg, RE, Al Saleem, T, Canutescu, AA, Dunbrack, RL, Jr., Serebriiskii, IG, Fang, R, Latypova, E, Hopkins, R, Vinson, C, Joung, JK, Golemis, EA: Couple-focused group intervention for women with early stage breast cancer. J. Consult. Clin. Psychol. 73:634-646., 2005.
95. Feigenberg SJ, Eisenberg D, Horwitz EM, Uzzo RG, Hanlon AL, Pollack A: Post-treatment PSA values within 6 months of 3D conformal radiotherapy for prostate cancer predict distant metastases. Int. J Rad Onc Bio Phys. 60 (1): S234-35, 2004.
96. Uzzo RG, Bramwell M: Renal cell carcinoma: The role of urologists in adjuvant strategies. Am J Urol Review: Supp 11, vol 12, 2004.
97. Horwitz EM, Feigenberg SJ, Pollack A, Hanks GE, Uzzo RG: re: Androgen suppression plus radiation therapy for prostate cancer. JAMA: 292 (17), 2084-85, 2004.
98. Yamaguchi K, Uzzo RG, Finke JH, Kolenko V: Renal carcinoma cells undergo apoptosis without oligonucleospmal DNA fragmentation. Biochem Biophys Res Commun. 318 (3):710, 2004.
99. Jacob R, Hanlon AL, Horwitz EM, Movsas B, Uzzo RG, Pollack A The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer. Cancer, 100(3): 538, 2004.
100. Kansas B, Eddy MJ, Mydlo JH, Uzzo RG: Incidence and management of penetrating renal trauma in patients with multi-organ injury: extended experience at an inner city trauma center. J Urol 172 (4):1355-60, 2004.
101. Horwitz EM, Feigenberg SJ, Uzzo RG: The treatment of non-metastatic prostate cancer with external beam radiation therapy. Minerv Urol. Nephrol. 56(2): 173-188, 2004.
102. Mueller TJ, Wu H, Greenberg RE, Hudes G, Topham N, Lessin SR, Uzzo RG: Cutaneous metastases from genitourinary malignancies Urol 63(6): 1021-6, 2004.
103. Uzzo RG: Re: Prostate Cancer – 3rd International Consultation on Prostate Cancer. BJU Int 93(6):885-886, 2004.
104. Dulaimi E, de Caceres I, Uzzo RG, Al-Saleem T, Greenberg RE, Polasick T, Babb JS, Cairns P: Promoter hypermethylation profile of kidney cancer. Clin Canc. Res. 10 (12): 3972-79, 2004.
105. Buyyounouski M, Horwitz E, Hanlon A, Uzzo R, Pollack A: Re: improved clinical staging system combining biopsy laterality and TNM stage for men with T1c and T2 prostate cancer: results from the search database. J Urol. 171(3): 1246, 2004.
106. Al-Saleem T, Cairns P, Dulaimi EA, Feder M, Testa JR, Uzzo RG: The genetics of renal oncocytosis: A possible model for neoplastic progression. Cancer Genet. Cytogenet. 152 (1):23-8, 2004.
107. Dulaimi E, Uzzo RG, Greenberg RE, Al-Saleem T, Cairns P: Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel. Clin. Cancer Res 15;10 (6):1887-93, 2004.
108. Uzzo RG, Brown JG, Horwitz EM, Hanlon A, Mazzoni S, Konski A, Greenberg RE, Pollack A, Kolenko VM, Watkins-Bruner D: Prevalence and patterns of self-initiated nutritional supplementation in men at high risk for prostate cancer. BJU Int 93 (7):955-960, 2004.
109. Pollack A, Hanlon AL, Horwitz EM, Feigenberg SJ, Uzzo RG, Hanks GE: Prostate cancer radiotherapy dose response: An update of the Fox Chase Experience. J Urol. 171 (3): 1132, 2004.
110. Buyyounouski MK, Horwitz EM, Price RA, Hanlon AL, Uzzo RG, Pollack A: Intensity modulated radiation therapy with MRI-simulation to reduce doses received by erective tissues during prostate cancer treatment. Int J Radiat Oncol Biol Phys. 58 (3):743-9, 2004.
111. Buyyounouski MK, Horwitz EM, Uzzo RG, Price RA, McNeeley SW, Azizi D, Hanlon AL, Milestone B, Pollack A: The radiation doses to erectile tissues defined with MRI- after intensity modulated radiation therapy or iodine-125 brachytherapy alone. Int. J. Radiation. Oncology. Biol. Phys. 59 (5): 1383-91, 2004.
112. Kramer NM, Horwitz EM, Uzzo RG, Hanlon AL, Hanks GE: Matched-cohort analysis of patients with prostate cancer followed with observation or treated with 3D conformal radiation therapy. Brit. J. Urol. 94 (1): 59-62, 2004.
113. Pollack A, Hanlon A, Horwitz EM, Feigenberg S, Uzzo RG, Price RA: Radiation therapy dose escalation for prostate cancer: A rationale for IMRT. World J. Urol. 21(4): 200, 2003.
114. Diefenbach MA, Hamrick N, Uzzo RG, Pollack A, Horwitz E, Greenberg R, Engstrom PE: Clinical, demographic and psychosocial correlates of complementary and alternative medicine use by men diagnosed with early-stage prostate cancer. J Urol. 170 (1): 166-169, 2003.
115. Pollack A, Hanlon AL, Movsas B, Hanks GE, Uzzo R, Horwitz E: Biochemical failure as a determinant of distant metastases and death in prostate cancer treated with radiotherapy. Int J. Radiation Oncology Biol Phys. 57 (1): 19-23, 2003.
116. Nguyen KH, Horwitz EM, Hanlon AL, Uzzo RG, Pollack A: Does short-term androgen deprivation substitute for radiation dose in the treatment of high-risk prostate cancer? Int J Radiat Oncol Biol Phys. 57(2): 377-83, 2003.
117. Battagli C, Uzzo RG, Dulaimi E, Krassenstein RE, Al-Saleem T, Greenberg RE, Cairns P: Detection of renal cancer in urine by a tumor suppressor gene hypermethylation panel. Cancer Res. 63:8695-8699, 2003.
118. Buyyounouski MK, Horwitz EM, Hanlon AL, Uzzo RG, Hanks GE, Pollack A: Positive prostate biopsy laterality and implications for staging. Urology 62:298-303, 2003.
119. Horwitz EM, Uzzo RG, Hanlon AL, Greenberg RE, Hanks GE, Pollack A: Modifying American Society for Therapeutic Radiology and Oncology Definition of biochemical failure to minimize influence of backdating in patients with prostate cancer treated with 3-dimensional conformal radiation therapy alone. J Urol. 169 (3): 2153-2159, 2003.
120. Horwitz EM, Mitra RK, Uzzo RG, Das IJ, Pinover WH, Hanlon AL, McNeeley SW, Hanks GE: Impact of target volume coverage with RTOG-98-05 guidelines for transrectal ultrasound guided permanent I-125 prostate implants. Radiother. Oncol. 66 (2):173-179, 2003.
121. Pinover WH, Horwitz EM, Hanlon AL, Uzzo RG, Hanks GE: Validation of a treatment policy for PSA failures following 3D conformal prostate radiation therapy. Cancer 97:1127-1133, 2003.
122. Uzzo RG, Pinover WH, Horwitz EM, Parlanti A, Mazzoni S, Raysor S, Mirchanandi I, Greenberg RE, Pollack A, Hanks GE, Watkins-Bruner D: Free PSA improves prostate cancer detection in a high risk population of men with a normal total PSA and digital rectal exam. Urology. 61 (4), 754-759, 2003.

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Research Summary

Medulloblastoma is the most common malignant brain tumor in children, and also occurs in adults. Despite significant progress in development of treatments for this cancer, the mortality rate of medulloblastoma is still very high. Our research seeks to elucidate the mechanisms of medulloblastoma initiation and progression, with the aim of translating the findings into improved strategies for the treatment of medulloblastoma.

To study the basis of medulloblastoma formation, we first focus on the tumor cell itself, to define what genetic and/or epigenetic events could convert a normal cell into a tumor cell. We are also examining the functions of tumor-supporting cells (the tumor stroma, and other constituents of the tumor microenvironment) in medulloblstoma formation. We hope to find a more effective way to control medulloblastoma growth, through targeting both tumor cells and their supporting stroma.

Selected Publications

1. Kessler JD, Hasegawa H, Brun SN, Emmenegger BA, Yang ZJ, Dutton JW, Wang F, Wechsler-Reya RJ. N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma. Genes Dev. 2009 Jan 15;23(2):157-70. PubMed
2. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schüller U, Machold R, Fishell G, Rowitch DH, Wainwright BJ, Wechsler-Reya RJ. Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell. 2008 Aug 12;14(2):135-45. PubMed
3. Yang ZJ, Wechsler-Reya RJ. Hit ‘em where they live: Targeting the cancer stem cell niche. Cancer Cell. 2007 Jan;11(1):3-5. PubMed
4. Yang ZJ, Appleby VJ, Coyle B, Chan WI, Tahmaseb M, Wigmore PM, Scotting PJ. Novel strategy to study gene expression and function in developing cerebellar granule cells. J Neurosci Methods. 2004 Jan 30;132(2):149-60. PubMed

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DNA Replication Fork Restart and Homology-Based DNA Double-Strand Break Repair

A hallmark of cancer cells is their inability to stably maintain genome. This defect accelerates the accumulation of mutations that promote the development of cancer. Paradoxically, it also renders cancer cells more sensitivity than normal cells to the most commonly used chemotherapeutic drugs, which act by damaging DNA. However, the intrinsic genetic diversity of cancer cells also dictates that some cancer cells might be resistant to drugs and eventually lead to recurrence. The research in my laboratory focuses on two major processes that have the most direct impact on genome maintenance: DNA double-strand break (DSB) repair and DNA lesion replication. These two processes have been extensively studied by genetic analysis and enzymatic characterization, but most of the fundamental mechanistic questions remain poorly understood. We take a biochemical approach: biochemical reconstitution of the reactions in cell-free extracts derived from the eggs of the frog Xenopus leavis, dissect the reaction mechanism at the DNA level, identify the critical proteins, and confirm the results in cells.

We have succeeded in reconstituting single-strand annealing (SSA), which along with homologous recombination (HR) constitute the homology-dependent pathways for DSB repair. Using this system, we have found that the Xenopus Werner syndrome protein (xWRN) plays a pivotal role in SSA, providing the first direct evidence to link this protein to a specific DNA repair pathway. Further analysis led us to the discovery of an xWRN-mediated pathway that processes DSBs into 3’ single-strand tails. We found that xWRN, as a RecQ-type DNA helicase, unwinds DNA ends. The 5’ ss-tail is then degraded by a specific nuclease, which we have purified and identified as the Xenopus DNA2 protein (xDNA2), leaving the 3’ ss-tail as the final product of end processing. Because DNA end processing is a key step for not only SSA but also HR, we are conducting a comprehensive study to identify additional proteins in this reaction. In addition, we are using the Xenopus system to determine the mechanistic roles of two well studied but still poorly understood repair proteins, Mre11 and CtIP, in end processing.

In addition to SSA, we have also succeeded in reconstituting the first in vitro system that uses eukaryotic replication forks to replicate a site-specific lesion. Analysis of this system has revealed many novel insights into lesion replication at the nucleotide level resolution. We are currently determining what proteins are important for lesion replication and how they act mechanistically. This should help elucidate the mechanism for how cells deal with damages in the genome.

Selected Publications

1. Fazlieva R, Spittle CS, Morrissey D, Hayashi H, Yan H, Matsumoto Y. Proofreading exonuclease activity of human DNA polymerase and its effects on lesion-bypass DNA synthesis. Nuclei Acids Res. 2009;37:2854-66. PubMed
2. Liao S, Toczylowski T, Yan H. Identification of the Xenopus DNA2 protein as a major nuclease for the 5' -> 3' strand-specific processing of DNA ends. Nucleic Acids Res. 2008;36:6091-100. PubMed
3. Liao SR, Matsumoto Y, Yan H. Biochemical Reconstitution of Abasic DNA Lesion Replication in Xenopus Extracts. Nucleic Acids Research. 2007;35:5422-9. PubMed
4. Toczylowski T, Yan H. Mechanistic Analysis of a DNA End Processing Pathway Mediated by the Xenopus Werner Syndrome Protein. J Biol Chem. 2006;281:33198-205. PubMed
5. Yan H, McCane J, Toczylowski T, Chen C. Analysis of the Xenopus Werner syndrome protein in DNA double-strand break repair. J Cell Biol. 2005;171:217-227. PubMed
6. Chen CY, Graham J, Yan H. Evidence for a replication function for FFA-1, the Xenopus ortholog of Werner syndrome protein. J. Cell Biol. 2001;152:985-996.

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Molecular Mechanisms that Maintain Genome Stability in Human Cells

Growth of multicellular organisms is critically dependent on the ability of individual cells to duplicate and separate their genomes during cell division. Defects in DNA replication and chromosome segregation can lead to significant human health problems that include cancer, birth defects and infertility. The mechanisms that are responsible for replicating the genome and to segregate the resultant chromosomes during mitosis can be viewed as mechanical events because the proteins involved in these functions are molecular machines. Superimposed on the mechanical processes are regulatory mechanisms called checkpoints that monitor the molecular machines to ensure that their tasks are accomplished accurately and in a timely manner. Thus, checkpoints play an essential role in maintaining genome stability by ensuring that errors in DNA replication and chromosome segregation are corrected before cells are allowed to divide.

Our laboratory is focused on understanding the mechanical and regulatory mechanisms that ensure that chromosomes are properly attached and segregated by the spindle during mitosis. We have focused our attention on characterizing the molecular composition and function of the kinetochore, as this is the structure on the chromosome that establishes and monitors connections with microtubules. We have identified molecular motors and checkpoint proteins that reside at kinetochores and are interested in understanding how these proteins interact with each other to carry out complex kinetochore functions. Our research is particularly relevant to cancer research as drugs that inhibit mitosis are a major modality for anti-cancer therapy. Current drugs however, lack specificity as they target microtubules that provide functions that not only are critical for mitosis but also for other essential cellular processes such as vesicle transport, cell shape and locomotion. Our studies of how chromosomes segregate have revealed novel proteins that provide functions that are critical only during mitosis. As such, these proteins should be ideal candidates for the development of highly specific anti-mitotic drugs.

Selected Publications

1. Beeharry N, Yen TJ. p53-dependent apoptosis in response to spindle damage linked to loss of Bub1. Cancer Biol Ther 2009; 8 (7). PubMed
2. Zhang XD, Goeres J, Zhang H et al. SUMO-2/3 modification and binding regulate the association of CENP-E with kinetochores and progression through mitosis. Mol Cell 2008; 29 (6):729-41. PubMed
3. Liu ST, Yen TJ. The kinetochore as target for cancer drug development. In: PD Wulf; WC Earnshaw, editors, translator and editor The Kinetochore from Molecular Discoveries to Cancer Therapy: Springer; 2008.
4. Huang H, Hittle J, Zappacosta F et al. Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit. J Cell Biol 2008; 183 (4):667-80. PubMed
5. Huang H, Fletcher L, Beeharry N et al. Abnormal cytokinesis after X-irradiation in tumor cells that override the G2 DNA damage checkpoint. Cancer Res 2008; 68 (10):3724-32. PubMed

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Research Interests

As Chief Academic Officer at Fox Chase, I focus on fostering academic collaborations and mentoring to augment the research potential of basic, translational, and clinical researchers.  Trained as a pathologist, my research background includes a focus on clinical decision-making.  In addition, my work promotes the application of advanced information technology to solve cutting-edge problems in biomedical sciences and health care.  Recent studies have focused on the systematic integration of biomarkers into the selection of patients for specific therapies, and the creation and support of databases to efficiently integrate multiple classes of data that inform the management of specific cancers, including prostate and colon cancer.  My work also integrates consideration of psychosocial factors as an important determinant of how patients best can be directed to appropriate therapies, supporting the overall Fox Chase goal of enhancing personalized medicine.

Selected Publications

Min H, Manion FJ, Goralczyk E, Wong YN, Ross E, Beck JR. Integration of prostate cancer clinical data using an ontology. J Biomed Inform. 2009 Dec;42(6):1035-45. Epub 2009 Jun 2.
1. Wong YN, Meropol NJ, Speier W, Sargent D, Goldberg RM, Beck JR. Cost implications of new treatments for advanced colorectal cancer. Cancer. 2009 May 15;115(10):2081-91.
2. Cárdenas-Turanzas M, Follen M, Nogueras-Gonzalez GM, Benedet JL, Beck JR, Cantor SB. The accuracy of the Papanicolaou smear in the screening and diagnostic settings. J Low Genit Tract Dis. 2008 Oct;12(4):269-75.
3. Cárdenas-Turanzas M, Nogueras-Gonzalez GM, Scheurer ME, Adler-Storthz K, Benedet JL, Beck JR, Follen M, Cantor SB. The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings. Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2865-71.
4. Cantor SB, Cárdenas-Turanzas M, Cox DD, Atkinson EN, Nogueras-Gonzalez GM, Beck JR, Follen M, Benedet JL. Accuracy of colposcopy in the diagnostic setting compared with the screening setting. Obstet Gynecol. 2008 Jan;111(1):7-14.
5. Konski A, Speier W, Hanlon A, Beck JR, Pollack A. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007 Aug 20;25(24):3603-8.
6. Cantor SB, Levy LB, Cárdenas-Turanzas M, Basen-Engquist K, Le T, Beck JR, Follen M. Collecting direct non-health care and time cost data: Application to screening and diagnosis of cervical cancer. Med Decis Making. 2006 May-Jun;26(3):265-72.
7. Jibaja-Weiss ML, Volk RJ, Friedman LC, Granchi TS, Neff NE, Spann SJ, Robinson EK, Aoki N, Robert Beck J. Preliminary testing of a just-in-time, user-defined values clarification exercise to aid lower literate women in making informed breast cancer treatment decisions. Health Expect. 2006 Sep;9(3):218-31.
8. Konski A, Watkins-Bruner D, Feigenberg S, Hanlon A, Kulkarni S, Beck JR, Horwitz EM, Pollack A. Using decision analysis to determine the cost-effectiveness of intensity-modulated radiation therapy in the treatment of intermediate risk prostate cancer. Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):408-15. Epub 2006 Aug 2.
9. Jibaja-Weiss ML, Volk RJ, Granch TS, Nefe NE, Spann SJ, Aoki N, Robinson EK, Freidman LC, Beck JR. Entertainment education for informed breast cancer treatment decisions in low-literate women: development and initial evaluation of a patient decision aid. J Cancer Educ. 2006 Fall;21(3):133-9.
10. Konski A, Sherman E, Krahn M, Bremner K, Beck JR, Watkins-Bruner D, Pilepich M. Economic analysis of a Phase III clinical trial evaluating the addition of total androgen suppression to radiation versus radiation alone for locally advanced prostate cancer (Radiation Therapy Oncology Group protocol 86-10). Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):788-94.

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Research Interests

Chemoprevention is a unique and promising strategy for reducing cancer risk through the administration of synthetic or dietary compounds. Further development of this important concept relies on the identification of compounds that have low toxicity and an understanding of their mechanisms of action. Administration of a dietary supplement that provides high-risk individuals with protection against cancer could significantly affect tumor incidence, mortality and morbidity.

Our research program focuses on the preclinical development of nutritional preventive regimens for individuals at increased risk for cancer. The overall goal is to contribute significantly to the prevention of tumorigenesis before it starts and/or the inhibition of tumor growth using naturally occurring compounds, such as nutrients.

Selected Publications

• Hensley HH, Merkel CE, W-CL Chang, K Devarajan, HS Cooper and ML Clapper. Endoscopic imaging and size estimation of colorectal adenomas in the Multiple Intestinal Neoplasia mouse. Gastrointest Endosc. 2009;69(3)Suppl:742-9. PubMed
• Clapper ML, Gary MA, Coudry RA, Litwin S, Chang W-CL, Devarajan K, Lubet RA Cooper HS. 5 aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2008;14:1341-7. PubMed
• Clapper ML, Cooper HS, Chang W-CL. Dextran sulfate sodium-induced colitis-associated neoplasia – A promising model for the development of chemopreventive interventions. In: Molecular Targets, Biomarkers and Animal Models for Anti-Cancer Pharmacological Research: Potentials and Challenges from Chemoprevention to Chemotherapeutics. A.N.T. Kong (ed.). Acta Pharmacol. Sin., 28:1450-1459, 2007. PubMed
• Chang W-CL, Coudry RA, Clapper ML, Zhang X, Williams K, Spittle CS, Li T, Cooper HS. Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis. 2007;28:2375-81. PubMed
• Wong Y-N, Chang W-C, Clapper M, Engstrom PF. Chemoprevention of colorectal cancer. In: Colorectal Cancer: Evidence-Based Chemotherapy Strategies. L.B. Saltz (ed.). Humana Press Inc., Totowa, NJ, pp. 33-49, 2006. PubMed
• Chang W-CL, Everley LC, Pfeiffer II, GR, Cooper HS, Barusevicius A, Clapper ML. Sulindac sulfone is most effective in modulating β-catenin-mediated transcription in cells with mutant APC. Ann NY Acad Sci. 2005 Nov;1059:41-55. PubMed
• Cooper HS, Chang W-C, Coudry R, Gary M, Everley L, Wang H, Litwin S, Clapper ML. Generation of a unique strain of multiple intestinal neoplasia (Apc+/Min-FCCC) mice with significantly increased numbers of colorectal adenomas. Mol Carcinog. 2005 Sep;44(1):31-41. PubMed

Selected Publications

1. Hensley HH, Merkel CE, W-CL Chang, K Devarajan, HS Cooper and ML Clapper. Endoscopic imaging and size estimation of colorectal adenomas in the Multiple Intestinal Neoplasia mouse. Gastrointest Endosc. 2009;69(3)Suppl:742-9.
2. Clapper ML, Gary MA, Coudry RA, Litwin S, Chang W-CL, Devarajan K, Lubet RA Cooper HS. 5 aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2008;14:1341-7.
3. Clapper ML, Cooper HS, Chang W-CL. Dextran sulfate sodium-induced colitis-associated neoplasia – A promising model for the development of chemopreventive interventions. In: Molecular Targets, Biomarkers and Animal Models for Anti-Cancer Pharmacological Research: Potentials and Challenges from Chemoprevention to Chemotherapeutics. A.N.T. Kong (ed.). Acta Pharmacol. Sin., 28:1450-1459, 2007.
4. Chang W-CL, Coudry RA, Clapper ML, Zhang X, Williams K, Spittle CS, Li T, Cooper HS. Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis. 2007;28:2375-81.
5. Wong Y-N, Chang W-C, Clapper M, Engstrom PF. Chemoprevention of colorectal cancer. In: Colorectal Cancer: Evidence-Based Chemotherapy Strategies. L.B. Saltz (ed.). Humana Press Inc., Totowa, NJ, pp. 33-49, 2006.
6. Chang W-CL, Everley LC, Pfeiffer II, GR, Cooper HS, Barusevicius A, Clapper ML. Sulindac sulfone is most effective in modulating β-catenin-mediated transcription in cells with mutant APC. Ann NY Acad Sci. 2005 Nov;1059:41-55.
7. Cooper HS, Chang W-C, Coudry R, Gary M, Everley L, Wang H, Litwin S, Clapper ML. Generation of a unique strain of multiple intestinal neoplasia (Apc+/Min-FCCC) mice with significantly increased numbers of colorectal adenomas. Mol Carcinog. 2005 Sep;44(1):31-41.
8. Lakshmi VM, Clapper ML, Chang W-C, Zenser TV. Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline to 2 nitrosoamino-3-methylimidazo[4,5-f]quinoline. Chem Res Toxicol. 2005;18:528-35.
9. Clapper ML, Coudry J, Chang W-CL. β-catenin-mediated signaling: A molecular target for early chemopreventive intervention. Mutat Res. 2004;555:97-105.
10. Hensley HH, Chang W-C, Clapper ML. Detection and volume determination of colonic tumors in Min mice by magnetic resonance micro-imaging. Magn Reson Med. 2004;52:524-9.
11. Xu M, Floyd HS, Greth SM, Chang W-CL, Lohman K, Stoyanova R, Kucera GL, Kute TE, Willingham MC, Miller MS. Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol. 2004;195:232-46.
12. Cooper HS, Everley L, Chang W-C, Pfeiffer G, Lee B, Murthy S Clapper ML. The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis. Gastroenterology. 2001;121:1407-16.
13. Hong MY, Chapkin RS, Morris JS, Wang N, Carroll RJ, Turner ND, Chang W-C, Davidson LA, Lupton JR. Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model. Carcinogenesis. 2001;22:1831-5.
14. Clapper ML, Chang W-C L, Meropol NJ. Chemoprevention of colorectal cancer. Current Opinion in Oncology. 2001;13:307-13.
15. Davidson LA, Brown RE, Chang W-C L, Morris JS, Wang N, Carroll RJ, Turner ND, Lupton JR, Chapkin RS. Morphodensitometric analysis of protein kinase C beta(II) expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis. Carcinogenesis. 2000;21:1513-9.
16. Lupton JR, Chang W-C L, Hong MY, Chapkin RS. Fat/fiber interactions on colonic cytokinetics: relationship to colon cancer. Asia Pacific J Clin Nutr. 1999;8:S37-40.
17. Lupton JR, Chang W-C L, Hong MY, Chapkin RS. Diet effects on apoptosis during colon carcinogenesis. Ann Acad Stud. 1998;37-40.
18. Chang W-C L, Chapkin RS, Lupton JR. Fish oil blocks azoxymethane-induced tumorigenesis by increased cell differentiation and apoptosis rather than decreased cell proliferation. J Nutr. 1998;128:491-7.
19. Chang W-C L, Chapkin RS, Lupton JR. Predictive value of proliferation, differentiation and apoptosis as intermediate markers for colon tumorigenesis. Carcinogenesis. 1997;18:721-30.
20. Hong MY, Chang W-C L, Chapkin RS, Lupton JR. Relationship among colonocyte proliferation, differentiation and apoptosis as a function of diet and carcinogen. Nutr Cancer. 1997;28:20-9.
21. Jiang Y-H, Lupton JR, Chang W-C L, Jolly CA, Aukema HM, Chapkin RS. Dietary fat and fiber differentially alter intracellular second messengers during tumor development in rat colon. Carcinogenesis. 1996;17:1227-33.
22. Lupton JR, Steinbach G, Chang W-C, O'Brien BC, Wiese S, Stoltzfus CL, Wargovich MJ, McPherson RS, Winn RJ. Calcium supplementation modifies the relative amounts of bile acids in bile and affects key aspects of colon physiology. J Nutr. 1996;126:1421-8.
23. Davidson LA, Lupton JR, Jiang Y-H, Chang WC, Aukema HM, Chapkin RS. Diet induced alteration of rat colon protein kinase C isozyme expression. J Nutr. 1995;125:49-56.
24. Aukema HA, Davidson LA, Chang W-C, Lupton JR, Derr JN, Chapkin RS. Dietary modulation of rat colonic cAMP-dependent protein kinase activity. Biochimica et Biophysical Acta. 1994;1224:51-60.
25. Chang W-C, Lupton JR, W. Frφlich GL, Schoeffler ML. Peterson, Chen X-Q. A very low intake of fat is required to decrease fecal bile acid concentrations in rats. J Nutr. 1994;124:181-7.

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Preclinical Chemoprevention: Biomarkers of Cancer Risk and Molecular Targets for Early Intervention

The overall goal of this program is to develop novel, efficacious therapeutic regimens for the prevention of human cancer. The major focus continues to be on the identification of early molecular alterations that may serve as biomarkers of cancer risk and targets for therapeutic intervention in colorectal and lung carcinogenesis.

Current efforts focus on four areas of basic research, which include: 1) identification of molecular targets for early intervention; 2) selection of the most promising chemopreventive agents for analysis and elucidation of their mechanism of action; 3) establishment of biomarkers of cancer risk to facilitate the selection of those asymptomatic high-risk individuals who would benefit most from a preventive intervention; and 4) the development of validated intermediate endpoints of carcinogenesis and their use as biomarkers of therapeutic response. Application of state-of-the-art genomic and imaging technology to the analysis of well-defined mouse models continues to provide unique insight into the molecular basis of the carcinogenic process and potential strategies for tumor inhibition.

Selected Publications

1. Meireles SI, Esteves GH, Hirata R Jr, Peri S, Devarajan K, Slifker M, Mosier SL, Peng J, Vadhanam MV, Hurst HE, Neves EJ, Reis LF, Gairola CG, Gupta RC, Clapper ML. Early changes in gene expression induced by tobacco smoke: evidence for the importance of estrogen within lung tissue. Cancer Prev Res (Phila). 2010 Jun;3(6):707-17. Epub 2010 Jun 1. PubMed
2. Hensley HH, Merkel CE, Chang W-CL, Devarajan K, Cooper HS, Clapper ML. Endoscopic imaging and size estimation of colorectal adenomas in the Multiple Intestinal Neoplasia mouse. Gastrointest Endosc. 2009;69(3)Suppl:742-9. PubMed
3. Shatalova EG, Klein-Szanto AJP, Devarajan K, Cukierman E, Clapper ML. Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis. Cancer Prev Res (Phila). 2011 Jan;4(1):107-15. PubMed
4. Chang W-CL, Coudry RA, Clapper ML, Zhang X, Williams K, Spittle CS, Li T, Cooper HS. Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis. 2007;28:2375-81. PubMed
5. Cooper HS, Chang W-C, Coudry R, Gary M, Everley L, Spittle CS, Wang H, Litwin S, Clapper ML. Generation of a unique strain of multiple intestinal neoplasia (Apc+/Min-FCCC) mice with significantly increased numbers of colorectal adenomas. Mol Carcinog. 2005; 44:31-41. PubMed

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Department of Clinical Genetics

The Risk Assessment Program at Fox Chase looks at your personal and possible inherited genetic factors that may put you at higher possibility for getting cancer. We comprehensively examine your profile for all cancer types, including — but not limited to — breast cancer, ovarian cancer, gastrointestinal cancers, prostate cancer, and melanoma. Knowing your risk helps you learn what you can do to lower your chances of getting cancer.

The Department of Clinical Genetics is built on the success of Fox Chase's Margaret Dyson Family Risk Assessment Program (now Risk Assessment Program), which Dr. Mary Daly began in 1991. A high-risk screening clinic was developed for individuals with a family history of breast or ovarian cancer. In addition to the clinic, genetic counseling was provided for both high risk and breast and ovarian cancer patients. As the clinic developed, it became clear that it was important to provide consultations for biopsy findings that put women at increased risk. Since then, Fox Chase has expanded risk assessment services to those at high risk for all cancers.

Building the Profile

A combination of your family history and your genetic data is used to build a profile of your risk for all cancer types, including — but not limited to — breast, ovarian, uterine, gastrointestinal (including colon), prostate, thyroid, and melanoma.

Research

The Department of Clinical Genetics is closely aligned with ongoing research initiatives including Fox Chase's Cancer Prevention and Control Program, as well as its Keystone Program in Personalized Risk and Prevention, a collaborative translational science program co-led by Daly and funded through philanthropic donations to Fox Chase.

Selected Publications

1. Domchek SM, Friebel TM, Garber JE, Isaacs C, Matloff E, Eeles R, Evans DG, RubinsteinW, Singer CF, Rubin S, Lynch HT, Daly MB, Weitzel J, Ganz PA, Pichert G, Olopade OI, Tomlinson G, Tung N, Blum JL, Couch F, Rebbeck TR. Occult Ovarian Cancers Identified at Risk-Reducing Salpingo-Oophorectomy in a Prospective Cohort of BRCA1/2 Mutation Carriers. Breast Cancer Res Treat. 2010 Feb 24 [Epub ahead of print] (PMCID in progress).
2. Petrucelli N, Daly MB, Feldman GL. Hereditary Breast and Ovarian Cancer Due to Mutations in BRCA1 and BRCA2. Genet Med. 2010 Mar 3 [Epub ahead of print] (PMCID in progress).
3. Bellacosa A, Godwin AK, Peri S, Devarajan K, Caretti E, Vanderveer L, Bove B, Slater C, Zhou Y, Daly M, Howard S, Campbell KS, Nicolas E, Yeung AT, Clapper ML, Crowell JA, Lynch HT, Ross E, Kopelovich L, Knudson AG. Altered Gene Expression in Morphologically Normal Epithelial Cells from Heterozygous Carriers of BRCA1 and BRCA2 Mutations. Cancer Prev Res 3(1):48-61, 2010. (PMCID: PMC2804937).

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Research Interests

Our primary area of research focuses on the relationship of hormones to cancer, particularly breast cancer and how health behaviors and genetics may affect cancer risk by modifying hormone levels. Breast cancer is a hormonally dependent cancer. Our prospective study of endogenous serum hormones and breast cancer risk in the Columbia, MO Serum Bank cohort (Dorgan JF et al, Cancer Epidemiol Biomarkers Prev, 1996;5:533) was among the first of several prospective epidemiologic studies to show an increased risk of breast cancer among postmenopausal women with elevated serum estrogen and androgen concentrations. In the pooled analysis of the world-wide data (Breast Cancer Collaborative Group, J Natl Cancer Inst 94:606, 2002), in which we participated, postmenopausal women with elevated serum estrogen and androgen levels were at an approximate 2-fold excess risk of developing breast cancer. Biomarker studies not only increase our understanding of cancer etiology, but also could identify women at increased risk. Furthermore, biomarkers associated with risk can be used as endpoints in trials to evaluate effectiveness of interventions to prevent cancer and improve outcomes. We continue to conduct research aimed at identifying biomarkers associated with breast cancer risk.

Numerous health behaviors including diet, alcohol ingestion, and physical activity could influence breast cancer risk through effects on serum hormones. In earlier cross-sectional analyses, we found that diet (Dorgan JF et al, Am J Clin Nutr 1996;64:25), alcohol ingestion (Dorgan JF et al, Cancer Causes Control, 1994;5:53; Garcia Closas M et al. Int J Cancer, 2002;102:172) and physical activity (Madigan MP et al. Cancer Causes Control, 1998;9:199) are associated with serum hormone levels in women. We more recently conducted a controlled feeding study of alcohol’s effects on serum biomarkers and found that consumption of 1-2 drinks per day increased serum levels of estrogens and androgens in postmenopausal women (Dorgan JF et al, J. Natl. Cancer Inst, 2001;93:710). Alcohol ingestion altered serum levels of several other serum biomarkers including insulin-like growth factor binding protein 3 (Lavigne JA et al. Am J Clin Nutr, 2005;81:503), leptin (Roth M et al, J Natl Cancer Inst 2003;95:1722), isoprostanes (Hartman TJ et al. Eur J Clin Nutr, 2005;59:161) and vitamin B12 (Laufer EM et al. Eur J Clin Nutr, 2004;58:1518). Thus, health behaviors likely contribute, at least in part, to breast cancer risk via effects on metabolism.

The association of body weight with breast cancer risk is complex. Whereas obesity decreases risk of breast cancer before menopause, it increases risk after menopause. The increased risk associated with breast cancer is partly explained by higher serum estrogens in heavier postmenopausal women. In a pooled analysis of prospective studies (Endogenous Hormones and Breast Cancer Collaborative Group, J Natl Cancer Inst, 2003;95:1218), we found that adjustment for serum estradiol concentration attenuated the association of body mass index with breast cancer risk. The decreased risk of breast cancer in obese premenopausal women has been attributed to a higher frequency of anovulatory menstrual cycles in these women. However, this would not explain the lower risk of premenopausal breast cancer associated with obesity in young prepubescent children. In our longitudinal analyses (Baer HJ et al, Cancer Epidemiol Biomarkers Prev, 2007;16:1880), pre-pubertal obesity was associated with serum dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) levels during puberty but not with estrogens or progesterone. Whether the differences observed affect breast cancer development is unclear.

Because most breast development occurs during adolescence, our studies focus not only on adult exposures but also on adolescent exposures. We previously found that a reduced fat diet lowered serum estrogens and progesterone in adolescent girls (Dorgan JF, J Natl Cancer Inst, 2003;95:132). With funding from NCI, we currently are following-up this finding and are investigating the long-term effects of adolescent diet on biomarkers in young women that are consistently associated with breast cancer risk in adults including serum hormones, bone mineral density and breast density.

The adrenal androgens DHEA and DHEAS are consistently positively associated with breast cancer risk. We reported increased risks associated with elevated levels of these hormones in premenopausal women (Sturgeon SR et al, Cancer Causes Controlm 2004;15:45) and in postmenopausal women (Dorgan JF et al, Cancer Epidemiol Biomarkers Prev, 1996;5:533; Breast Cancer Collaborative Group, J Natl Cancer Inst, 2002;94:606). Furthermore, we found that both the adrenals and ovaries contribute to serum androstenedione levels that are associated with breast cancer risk in postmenopausal women (Dorgan JF et al, Cancer Epidemiol Biomarkers Prev, 2001;10:407). Adrenal steroid production is relatively stable in individual women over time suggesting that genetics likely plays a major role in regulating adrenal steroidogenesis. In a DOD funded pilot study, we found that response to corticotrophin (ACTH) stimulation varied by genotype of several genes involved in adrenal steroidogenesis (Dorgan JF et al, Endocrine submitted 2009). One participant who was the sole carrier of specific haplotypes in the ACTH receptor gene (MC2R) and in the steroid acute regulatory protein (StAR) gene exhibited a particularly exuberant response as evidenced by rapid increases in cortisol, DHEA and progesterone to higher levels than observed for other participants. Three other participants carried the putative functional T-34C SNP in CYP17. All three exhibited enhanced cortisol responsivity to ACTH, while 2 participants also had an increased DHEA response.

Adrenal steroidogenesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates homeostasis under basal conditions. The HPA axis also is the primary effectors of the physiologic response to psychological, social, metabolic, and physical stressors. Thus the HPA is a key determinant of physiological responses to diverse environmental exposures. In an NIH funded pilot study, we are beginning to evaluate the effects of psychosocial, behavioral and genetic characteristics on stress responsivity.

Selected Publications

1. Gaudet MM, Falk RT, Gierach GL, Lacey JV, Jr, Graubard BI, Dorgan JF, Brinton LA. Do adipokines underlie the association between known risk factors and breast cancer among a cohort of U.S. women? Cancer Epidemiol Jun 23 2010, epub ahead of publication.
2. Dorgan JF, Liu L, Klifa C, Hylton N, Shepherd JA, Stanczyk FZ, Snetselaar LG, Van Horn L, Stevens VJ, Robson A, Kwiterovich PO, Lasser NL, Himes JH, Pettee Gabriel K, Kriska A, Ruder EH, Fang CY, Barton, BA. Adolescent Diet and Subsequent Serum Hormones, Breast Density and Bone Mineral Density in Young Women: Results of the Dietary Intervention Study in Children (DISC) Follow-Up Study. Cancer Epidemiol Biomarkers Prev. 2010;19:1545-56.
3. Ruder EH, Hartman TJ, Rovine MJ, Dorgan JF. Birth Characteristics and Age at Menarche: Results from the Dietary Intervention Study in Children (DISC). Cancer Causes Control. 2010;21:1379-86.
4. Egleston BL, Chandler DW, Dorgan JF. Validity of estimating non-SHBG bound testosterone and estradiol from total hormone measurements in boys and girls. Ann Clin Biochem. 2010;47:233-41.
5. Kerver JM, Gardiner JC, Dorgan JF, Rosen CJ, Velie EM. Dietary predictors of the insulin-like growth factor system in adolescent girls: results from the Dietary Intervention Study in Children (DISC). Am J Clin Nutr. 2010;91:643-50.
6. Dorgan JF, Stanczyk FZ, Egleston BL, Kahle LL, Shaw CM, Spittle CS, Godwin AK, Brinton LA. Serum Müllerian Inhibiting Substance and Breast Cancer Risk. J Natl Cancer Inst. 2009;101:1501-9.
7. Dorgan JF, Spittle CS, Egleston BL, Shaw CM, Kahle LL, Brinton LA. Assay reproducibility and within-person variation of Mullerian inhibiting substance. Fertility Sterility. 2009;94:301-4.
8. McSorley MA, Alberg AJ, Allen DS, Allen NE, Brinton LA, Dorgan JF, Kaaks R, Rinaldi S, Helzlsouer KJ. Pre-diagnostic circulating follicle stimulating hormone (FSH) concentrations and ovarian cancer risk. Int J Cancer. 2009;125:674-9.
9. Fang CY, Egleston BL, Brown KM, Lavigne JV, Stevens VJ, Barton BA, Chandler DW, Dorgan JF. Family cohesion moderates the relation between free testosterone and delinquent behaviors in adolescent boys and girls. J Adolescent Health. 2009;44:590-7.
10. Ruder EH, Dorgan JF, Kranz S, Kris-Etherton PM, Hartman TJ. Examining breast cancer lifestyle risk factors: early life and childhood. Clinical Breast Cancer. 2008;8:334-42.
11. Endogenous Hormones and Prostate Cancer Collaborative Group. Endogenous sex hormones and prostate cancer: A collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008,100:170-83.
12. Baer HJ, Colditz GA, Willett WC, Dorgan JF. Adiposity and sex hormones in girls. Cancer Epidemiol Biomarkers Prev. 2007;16:1880-8.
13. McSorley MA, Alberg AJ, Allen DS, Allen NE, Brinton LA, Dorgan JF, Pollack M, Tao Y, Helzlsouer KJ. C-Reactive Protein Concentrations and Subsequent Ovarian Cancer Risk: A Multicenter Cohort Study. Obstetrics and Gynecology. 2007;109: 933-41.
14. Mahabir S, Baer DJ, Johnson LL, Hartman TJ, Dorgan JF, Campbell WS, Clevidence BA, Taylor PR. Usefulness of body mass index as a sufficient adiposity measurement for sex hormone concentration associations in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2006;15:2502-7.
15. Gidding SS, Barton BA, Dorgan JF, Kimm SY, Kwiterovich PO, Lasser NL, Robson AM, Stevens V, Van Horn L, Simons-Morton DG. Higher Self Reported Physical Activity is Associated with Lower Blood Pressure and LDL-cholesterol: The Dietary Intervention Study in Childhood (DISC). Pediatrics. 2006;118:2388-93.
16. Dorgan JF, McMahon RP, Friedman LA, Snetselaar LG, Van Horn L, Kwiterovich PO, Lauer RM, Lasser NL, Stevens VJ, Robson A, Greenhut SF, Chandler DW, Franklin FA, Barton BA, Patterson BH, Taylor PR, Schatzkin A. Diet and Sex Hormones in Boys: Findings from the Dietary Intervention Study in Children. J Clin Endo Metab. 2006;91:3992-6.
17. Mahabir S, Baer DJ, Johnson LL, Frenkel K, Dorgan JF, Campbell W, Hartman TJ, Clevidence B, Albanes D, Judd JT, Taylor PR. No association between alcohol supplementation and autoantibodies to DNA damage in postmenopausal women in a controlled feeding study. Eur J Cancer Prev. 2005;14:427-9.
18. Lavigne JA, Baer DJ, Wimbrow HH, Albert PS, Brown ED, Judd JT, Campbell WS, Giffen CA, Dorgan JF, Hartman TJ, Barrett JC, Hursting SD, Taylor PR. Effects of alcohol on insulin-like growth factor-I and insulin-like growth factor binding protein-3 in postmenopausal women. Am J Clin Nutr. 2005;81:503-7.
19. Hartman TJ, Baer DJ, Graham LB, Stone WL, Gunter EW, Parker CE, Albert PS, Dorgan JF, Clevidence BA, Campbell WS, Tomer KB, Judd JT, Taylor PR. Moderate alcohol consumption and levels of antioxidant vitamins and isoprostanes in postmenopausal women. Eur J Clin Nutr. 2005;59:161-8.
20. Mahabir S, Baer DJ, Johnson LL, Dorgan JF, Campbell W, Brown E, Hartman TJ, Clevidence B, Albanes D, Judd JT, Taylor PR. The effects of moderate alcohol supplementation on estrone sulfate and DHEAS in postmenopausal women in a controlled feeding study. Nutr J. 2004;3:11.
21. Laufer EM, Hartman TJ, Baer DJ, Gunter EW, Dorgan JF, Campbell WS, Clevidence BA, Brown ED, Albanes D, Judd JT, Taylor PR. Effects of moderate alcohol consumption on folate and vitamin B(12) status in postmenopausal women. Eur J Clin Nutr. 2004;58:1518-24.
22. Dorgan JF, Boakye NA, Fears TR, Schleicher RL, Helsel W, Anderson C, Robinson J, Guin JD, Lessin S, Ratnasinghe LD, Tangrea JA. Serum carotenoids and α-tocopherol and risk of non-melanoma skin cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1276-82.
23. Sturgeon SR, Potischman N, Malone KE, Dorgan JF, Daling J, Schairer C, Brinton LA. Serum levels of sex hormones and breast cancer risk in premenopausal women: a case-control study. Cancer Causes and Control. 2004;15:45-53.
24. Endogenous Hormones and Breast Cancer Collaborative Group. Free estradiol and breast cancer risk in postmenopausal women: Comparison of measured and calculated values. Cancer Epidemiol Biomarkers Prev. 2003;12:1457-61.
25. Roth M, Baer D, Albert PS, Castonguay TW, Dorgan JF, Dawsey SM, Brown ED, Hartman TJ, Campbell W, Giffen C, Judd JT, Taylor PR. The association between serum leptin and alcohol consumption in a controlled feeding and alcohol ingestion study. J Natl Cancer Inst. 2003;95:1722-5.
26. Endogenous Hormones and Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218-26.
27. Watkins Bruner D, Moore D, Parlanti A, Dorgan JF, Engstrom P. Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis. Int J Cancer. 2003;107:797-803.
28. Lamar CA, Dorgan JF, Longcope C, Stanczyk FZ, Falk RT, Stephenson HE. Serum Sex Hormones and Breast Cancer Risk Factors in Postmenopausal Women. Cancer Epidemiol Biomarkers Prev. 2003;12:380-3.
29. Van Horn L, Obarzanek E, Barton BA, Stevens VJ, Kwiterovich PO Jr, Lasser NL, Robson AM, Franklin FA Jr, Lauer RM, Kimm SYS, Dorgan JF, Greenlick MR. A summary of results of the Dietary Intervention Study in Children (DISC): lessons learned. Cardiovascular Nurs J. 2003;28:28-41.
30. Dorgan JF, Hunsberger SA, McMahon RP, Kwiterovich PO, Lauer RM, Van Horn L, Lasser NL, Stevens VJ, Friedman LA, Yanovski JA, Greenhut SF, Chandler DW, Franklin FA, Barton BA, Buckman DW, Snetselaar LG, Patterson BH, Schatzkin A, Taylor PR. Diet and sex hormones in girls: findings from a randomized controlled clinical trial. J Natl Cancer Inst. 2003;95:132-41.
31. Zhang Y, Kiel DP, Ellison RC, Schatzkin A, Dorgan JF, Kreger BE, Cupples A, Felson DT. Bone mass and the risk of prostate cancer: the Framingham Study. Am J Med. 2002;113:734-739.
32. Garcia-Closas M, Herbstman J, Schiffman M, Glass A, Dorgan JF. Relationship between serum hormone concentrations, reproductive history, alcohol consumption and genetic polymorphisms in pre-menopausal women. Int J Cancer. 2002;102:172-8.
33. Djoussé L, Dorgan JF, Zhang Y, Schatzkin A, Hood M, D’Agostino RB, Copenhafer D, Kreger BE, Ellison RC. Alcohol consumption and risk of lung cancer: The Framingham Study. J Natl Cancer Inst. 2002;94:1877-82.
34. Dorgan JF, Baer D, Albert P, Judd JT, Brown ED, Corle D, Campbell WS, Hartman TJ, Tejpar AA, Clevidence BA, Giffen CA, Chandler DW, Stanczyk FZ, Taylor PR. Serum hormones and the alcohol-breast cancer association in postmenopausal women. Menopause Digest. 2002;14:15-17.
35. Dorgan JF, Fears T, McMahon RP, Friedman LA, Patterson B, Greenhut S. Measurement of sex hormones in serum: a comparison of radioimmunoassay and mass spectrometry. Steroids. 2002;67:151-8.
36. Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: collaborative re-analysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606-16.
37. Dorgan JF, Baer D, Albert P, Judd JT, Brown ED, Corle D, Campbell WS, Hartman TJ, Tejpar AA, Clevidence BA, Giffen CA, Chandler DW, Stanczyk FZ, Taylor PR. Serum hormones and the alcohol-breast cancer association in postmenopausal women. J Natl Cancer Inst. 2001;93:710-5.
38. Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate. 2001;46:33-38.
39. Dorgan JF, Boudou P, Stanczyk FZ, Longcope C, Tejpar A, Falk RT, Schussler N, Stephenson HE Jr. Sources of elevated serum androgens in postmenopausal women who develop breast cancer. Cancer Epidemiol Biomarkers Prev. 2001;10:407-10.
40. Zhang Y, Felson DT, Ellison C, Kreger BE, Schatzkin A, Dorgan JF, Cupples LA, Levy D, Kiel DP. Bone mass and the risk of colon cancer among post-menopausal women: the Framingham Study. Am J Epidemiol. 2001;53:31-37.
41. Obarzanek E, Kimm SYS, Barton BA, Van Horn L, Kwiterovich PO Jr, Simons-Morton DG, Hunsberger SA, Lasser NL, Robson AM, Franklin FA Jr, Lauer RM, Stevens VJ, Friedman LA, Dorgan JF, Greenlick MR on behalf of the DISC Collaborative Research Group. Long-term safety and efficacy of a cholesterol-lowering diet in children: seven-year results of the Dietary Intervention Study in Children (DISC). Pediatrics. 2001;107:256-64.
42. McShane LM, Midthune DN, Dorgan JF, Freedman LS, Carroll RJ. Covariate measurement error adjustment for matched case-control studies. Biometrics. 2001;57:62-73.

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Research Interests

As a medical oncologist treating patients with gastrointestinal malignancies, I encounter the need for new treatment approaches on a daily basis. The medical community has had a long-term interest in liver-directed therapies for colon cancer with liver metastasis. My ongoing phase II clinical trial using drug-eluting irinotecan beads tests a novel modality of treatment for unresectable, liver-predominant, metastatic colon cancer. There is also increasing interest in the role of Aurora kinase A as a contributing oncogene in the tumorigenesis of colon cancer. I am collaborating with other investigators at Fox Chase Cancer Center  to study the prognostic significance of increased Aurora A gene copy number in metastatic colon cancer.

I am also interested in studying the treatment and outcomes of elderly oncology patients. Treatment of this patient population is very challenging, and requires special attention and consideration. Limited tools are available to help the oncologist in identifying those patients who are more likely to suffer significant toxicity with chemotherapy. In an attempt to identify useful biologic markers that can help oncologists, I am studying the correlation between telomere length and chemotherapy tolerance among elderly oncology patients.

Selected Publications

1. Dotan E, Cohen SJ. Challenges in the management of stage II colon cancer. Seminars in Oncology Jan 2011 - in press.
2. Dotan E, Cohen R. The ongoing roll-out of aurora kinase inhibitors in cancer treatment. Drugs of the Future 2010 – in press
3. Dotan E, Goldstein LJ. Optimizing chemotherapy regimens for patients with early-stage breast cancer. Clin Breast Cancer. 2010;10 Suppl 1:E8-15. PubMed
4. Dotan E, Aggarwal C, Smith MR. Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin's Lymphoma. P T. 2010 Mar;35(3):148-57. PubMed
5. Dotan E, Cohen SJ, Alpaugh KR, Meropol NJ. Circulating tumor cells: evolving evidence and future challenges. Oncologist. 2009 Nov;14(11):1070-82. Epub 2009 Nov 6. PubMed

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Biobehavioral Oncology and Health Disparities

Our laboratory aims to identify biobehavioral factors that influence cancer risk in a variety of populations. Guided by a biobehavioral model of cancer stress and disease course, we incorporate the use of comprehensive psychosocial assessments along with cutting-edge molecular techniques in our interdisciplinary research program. In particular, our laboratory has been focused on investigating biobehavioral mechanisms that may contribute to enhanced health outcomes in HPV-related cancers, such as cervical cancer and head and neck cancers. Other related projects examine cultural, psychosocial and environmental determinants of cancer health disparities in underserved Asian Americans. Together, these studies will lead to a greater understanding of how psychosocial, behavioral and biological factors interact to influence cancer risk and disease progression.

Selected Publications

1. Fang CY, Longacre ML, Manne SL, Ridge JA, Lango MN, Burtness BA. Informational needs of head and neck cancer patients. Health and Technology, 2(1);57-62, 2012. PubMed
2. Longacre ML, Ridge JA, Burtness BA, Galloway TJ, Fang CY. (2012). Psychosocial functioning of caregivers for head and neck cancer patients. Oral Oncology, 48, 18-25. PubMed
3. Tseng M, Fang CY. (2011). Stress is associated with unfavorable patterns of dietary intake among female Chinese immigrants. Annals of Behavioral Medicine, 41, 324-332. PubMed
4. Fang CY, Ma GX, Tan Y. Overcoming barriers to cervical cancer screening among Asian American women. (2011). North American Journal of Medicine and Science, 4(2), 77-83. PubMed
5. Fang CY, Reibel DK, Longacre ML, Rosenzweig S, Campbell DE, & Douglas SD. (2010). Enhanced psychosocial well-being following participation in a mindfulness-based stress reduction program is associated with increased natural killer cell activity. Journal of Alternative and Complementary Medicine, 16(5): 531-538. PubMed
6. Fang CY, Coups EJ, & Heckman CJ. (2010). Behavioral correlates of HPV vaccine acceptability in the 2007 Health Information National Trends Survey (HINTS). Cancer Epidemiology, Biomarkers & Prevention, 19(2): 319–26. PubMed

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Office of Health Communications and Health Disparities

The goal of the Office of Health Communications and Health Disparities (OHCHD) is to provide cancer education, screening and outreach services to the community and serve as a bridge to connect the community to our cancer prevention and control research. Our efforts are built on public health approaches and practices as well as a variety of dissemination and health behavior frameworks. We are committed to providing proven programs that increase knowledge about cancer and help individuals to take the appropriate actions to protect their health. Our screening programs are of the highest quality and bring important services to the communities’ doorsteps. Recognizing that our goals will only be accomplished in collaboration with organizations in the community, we develop and support ongoing partnerships to ensure our programs and services meet the needs of those we are trying to reach. We are involved in projects focused on cancer prevention & awareness, patient navigation, health literacy, and patient decision support as well as building capacity of community-based organizations to implement the most up-to-date cancer education programs in their community. Our projects and initiatives reach throughout Pennsylvania, Delaware and New Jersey and our staff work closely with colleagues from across the country.

The OHCHD believes that the integration of service and research is essential in community-based research. We are interested in adapting tested interventions and developing new approaches to reach populations that have been underserved or share an unequal burden of cancer, including racial and ethnic minorities, the elderly and those living in rural populations. Our research projects span health disparities, cancer communications and informed decision making with a strong foundation in the important role of communities and patients. Many of our research projects rely on community-based participatory research principles and approaches. In addition to our own initiatives, we have well established collaborations with other researchers to provide consultation and support on community-based research. These inter-related education, outreach and community- based research projects provide a coordinated approach to address the needs of patients, the general public and community organizations.

We carefully evaluate our programmatic efforts and believe it is important to share the results of our programs and research with other professionals and with the community at large. We have peer-reviewed publications and scientific presentations but also develop materials to share the results in a meaningful way to our communities and partners. Ensuring that the public and patients understand what they can do to protect their health is critical to our goals with the ultimate goal of long term capacity building and sustainability.

Selected Publications

1. Meropol NJ, Egleston BL, Buzaglo JS, Benson AB, Cegala DJ, Diefenbach MA, Fleisher L, Miller SM, Sulmasy DP, Weinfurt KP. Cancer Patient Preferences for Quality and Length of Life. Cancer. 2008;113:3459-66. PubMed
2. Fleisher L, Buzaglo J, Collins M, Millard J, Miller SM, Egleston B, Solarino N, Trinastic J, Cegala DJ, Benson AB, Schulman KA, Weinfurt KP, Sulmasy D, Diefenbach MA, Meropol NJ. Using Health Communication Best Practices to Develop a Web-Based Provider-Patient Communication Aid: The CONNECT StudyTM. Patient Education and Counseling 2008;71:378-387. PubMed
3. Kreps GL, Bright MA, Fleisher L, Marcus A, Morra ME, Perocchia RS. Future Directions for the Cancer Information Service and Cancer Education. Journal of Cancer Education, 2007;22(Suppl. 1):S70-73. PubMed
4. Fleisher L, Kornfeld J, Davis S, Morra ME, Squiers L. The NCI’s Cancer Information Service’s Research Continuum Framework: Integrating Research into Cancer Education Practice (1999-2004). Journal of Cancer Education. 2007;22(Suppl. 1):S41-8. PubMed
5. Myers RE, Berry A, Bradley P, Cocroft J, Daskalakis C, Delmoor E, Fleisher L, Kasper-Keintz M, Witt D. Increasing Access to Clinical and Educational Studies. Cancer. 2006;107(8):1962-70. PubMed
6. Bass SB, Ruzek SB, Fleisher L, McKeown-Conn N, Gordon T, Moore D. Relationship of Internet Health Information Use with Patient Behavior and Self-Efficacy: Experiences of newly diagnosed cancer patients who contact the National Cancer Institute’s Cancer Information Service. Journal of Health Communication. Journal of Health Communication. 2006;11:1-18. PubMed

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Research Interests

In common with other members of the Risk Assessment Program (RAP) and the Cancer Prevention and Control Program, my research team focuses on the impact of risk assessment coupled with genetic testing on cancer prevention. To this end, our research efforts include studying how patients understand their risk of cancer, especially when that risk is increased due to an inherited genetic mutation in a high-penetrance cancer risk gene (like a mismatch repair mutation in Lynch syndrome) or a low-penetrance cancer risk genetic marker (e.g. a single nucleotide polymorphism or SNP), how patient use available and emerging genetic technologies to better understand their risk of cancer, how genetic information diffuses within the population, and social disparities related to availability and uptake of genetic services in the general and high-risk population. With expertise in gastrointestinal (GI) oncology, clinical genetics, and epidemiology, I predominantly examine individuals at risk of gastrointestinal cancers, but have several ongoing collaborative studies that examine other high-risk populations.

Research examining the uptake and diffusion of commercial genetic testing for BRCA1/2 and the mismatch repair genes associated with Lynch syndrome has been the central focus of my efforts since 2007. This work has been generously funded by a career development award from the American Cancer Society. Two ongoing studies under this grant are examining aspects of genetic information diffusion within families, and a third will examine the impact of a tailored intervention to augment diffusion. Recent collaborative work with Dr. David Weinberg (FCCC, Gastroenterology) and others has examined how (that is, by what pathways) efforts to improve patient decisions act, and race and education as predictors of uptake of a gene-environment risk assessment test. Ongoing collaborative work with Dr. Wen-Chi Chang (FCCC Cancer Prevention and Control faculty) examines the efficacy of a chemopreventive agent (blackberry extract) in suppressing adenoma formation in a mouse model.

My research endeavors are also highly integrated into those of other researchers in RAP. Funding from the Greenwall foundation is currently supporting a study (co-investigator Dr. Angela Bradbury, Breast-Ovarian Risk Assessment) examining how cancer patients and their first-degree relatives think about new and emerging genomic tests, their preferences for informed consent, and how they perceive the importance of discussing genetic results with family members. Two collaborative studies with Dr. Veda Giri (Prostate Risk Assessment) are examining aspects of the high-risk prostate cancer population, including racial/ethnic disparities in uptake of screening colonoscopy and how to improve understanding of genomic tests for prostate cancer risk in a diverse population of men.

Selected Publications

1. Hall MJ, Reid JA, Wenstrup RT. Prevalence of BRCA1 and BRCA2 mutations in women with carcinoma in situ in women referred for genetic testing. Forthcoming 2010.
2. Hall MJ, Manne SL, Winkel G, Chung DS, Weinberg DS, Meropol NJ. Effects of a decision support intervention on decisional conflict associated with microsatellite instability testing. Forthcoming 2010.
3. Hall MJ, Buzaglo JS, Egleston B, Millard J, Miller SM, Meropol NJ. Barriers to participation in cancer prevention clinical trials Acta Oncol. 2010 Aug;49(6):757-66. PubMed
4. Hall MJ. Point-Counterpoint: Implementing population genetic screening for Lynch syndrome among newly diagnosed colorectal cancer patients—will the ends justify the means? J Natl Comp Canc Netw 2010;8(5):606-11. PubMed
5. Hall MJ, Manne SL, Myers RE, Keenan EM, Weinberg DS. Predictors of uptake of gene environment risk assessment (GERA) testing. 4th National Conference on Genomics and Public Health. Bethesda, MD (Dec 8-10th, 2010).
6. Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, Wenstrup RJ, Ward BE, Scholl TA, Noll WW. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer Cancer. Cancer. 2009 May 15;115(10):2222-33. PubMed
7. Forman A, Hall MJ. Influence of ethnicity on genetic counseling and testing for hereditary breast and ovarian cancer. Breast J 2009.S1:56-62. PubMed
8. Hall MJ. Genetic services have value beyond BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev. 2009;18(2):750. PubMed

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Cancer Risk and Risk-Reduction Behaviors

Dr. Heckman's research program goals are to develop, evaluate, and disseminate innovative interventions to improve cancer risk and risk-reduction behaviors. Her current focus is on primary prevention of skin cancer, and a second interest area is tobacco cessation. Dr. Heckman is a licensed counseling psychologist and runs FCCC's employee and family tobacco cessation program (ASAP: the All Smoking Aside Program), she is also a staff member in the patient Tobacco Treatment Program (TTP).

Dr. Heckman has several projects funded by the NCI and ACS:

• NCI R01: A Tailored Internet Intervention for Skin Cancer Risk Reduction among Young Adults
• NCI R21 Project BRITE: Biopsychosocial Relationships in Indoor Tanning Experiences among young women
• NCI R03 Project INCITE: Identifying Novel Correlates of Indoor Tanning Experiences among young women

Selected Publications

1. Heckman CJ, Zhu F, Kloss JD, Manne SL, Collins B, Bass SB, & Lessin SL (in press). Process and outcomes of a skin protection intervention for young adults. Journal of Health Psychology.
2. Heckman CJ, Darlow S*, Cohen-Filipic J, Kloss JD, Manne SL, Munshi T, Perlis, C. Psychosocial Correlates of Sunburn among Young Adult Women. International Journal of Environmental Research and Public Health, Special Issue – Sunbathing Habits and Skin Cancer. 2012; June;9(6):2241-2251.
3. Heckman CJ, Fang, CY, Jayo, I. Health behaviors associated with HPV vaccination among adolescents. Journal of Primary Care and Community Health. 2012 July; 3(3):170 - 173. Epub 2012 Jan 6.
4. Heckman CJ, Cohen-Filipic, J. Ultraviolet Radiation Exposure, Considering Acculturation Among Hispanics (Project URECAH). Journal of Cancer Education. 2012; June;27(1):342-346. Epub 2012 Jan 7. PubMed
5. Heckman CJ, Dykstra JL*, Collins BN. Substance-related knowledge, attitude, and behavior among college students: Opportunities for health education. Health Education Journal. 2011 Dec; 70(4):383-99. NIHMS 211929. PubMed
6. Coups EJ, Manne SL, Jacobsen PB, Ming ME, Heckman CJ, and Lessin SL. Skin surveillance intentions among family members of patients with melanoma. BMC Public Health. 2011 Nov;11:866. PMC3248224. PubMed
7. Heckman CJ, Manne SL, Kloss JD, Bass SB, Collins BN, Lessin SR. Beliefs and intentions for skin protection and exposure. American Journal of Health Behavior. 2011 Nov;35(6):699-711. NIHMS 197846. PubMed
8. Heckman CJ and Coups EJ. Correlates of sunscreen use among high school students: A cross-sectional survey. BMC Public Health. 2011 Aug;11:679. PMID:21884577. PMCID: PMC3179453. PubMed
9. Ingersoll KI, Farrell-Carnahan L, Cohen-Filipic J, Heckman CJ, Hettema J, Ceperich SD, Marzani-Nissen G (2011). A pilot randomized clinical trial of two medication adherence and drug use interventions for HIV+ crack cocaine users. Drug and Alcohol Dependence. Jul 1;116(1-3):177-87. Epub 2011 Feb 8. PubMed
10. Manne SL, Coups EJ, Jacobsen P, Ming M, Heckman CJ, Lessin SR. Sun protection and sunbathing practices among at-risk family members of patients with melanoma. BMC Public Health. 2011 Feb 21;11:122. PubMed

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Tobacco Control

Dr. Lazev is an Assistant Research Professor in the Cancer Prevention and Control Program. Her research program focuses on tobacco control with an emphasis on special populations, including pregnant/postpartum women, low-income and minority populations, college students, persons living with HIV/AIDS and cancer patients. Her research has been funded by the American Lung Association, the American Cancer Society, Pfizer and the American Society of Preventive Oncology/Cancer Research and Prevention Foundation. Dr. Lazev also co-directs the All Smoking Aside Program (ASAP) which provides smoking cessation services to employees and their families.

1. Pfizer Global Research Awards for Nicotine Dependence (GRAND)

A New Treatment for Smokers with High Negative Affect

Smokers are interested in, and motivated to, quit smoking. However, only 4-5% of those who make a quit attempt are successful at maintaining cessation. An important subgroup of smokers, those with high negative affect (e.g., depression), have an especially difficult time quitting smoking and maintaining abstinence. Negative affect and nicotine withdrawal (i.e., depression, sleep disturbance, difficulty concentrating, increased appetite, and weight gain) have been identified as key factors driving relapse to smoking. Light therapy, which targets hormones (melatonin) and chronobiology (circadian rhythms), has been empirically validated for treatment of depression including depressed mood, sleep disturbances, increased appetite, and cognitive difficulties. Dr. Lazev is currently investigating the ability of light therapy to reduce negative affect and the symptoms of nicotine withdrawal in order to increase success in smoking cessation.

2. American Society of Preventive Oncology Cancer Prevention Research Fellowship

College Student Situational Smoking: Trajectories & Cessation Barriers

Smoking is the single greatest cause of preventable mortality and morbidity in this country. The smoking rate among college students, who make up over a third of the 18-24 year old population, has been increasing at an alarming rate. This increase is in stark contrast to the smoking rate seen in adults with a college degree and suggests that if current college students do not quit smoking, the smoking rate among adults will increase in the future. Dr. Lazev’s prior research shows that among college students who smoke, one-half do not fit the typical smoking “phenotype” (e.g., categorization of smoker in terms of smoking-related behaviors and associated psychosocial variables). In the current study, Dr. Lazev is examining smoking behaviors and patterns to more systemically and comprehensively characterize smoking behavior among college students.

Selected Publications

1. Egleston BL, Cropsey KL, Lazev AB, Heckman CJ. A tutorial on principal stratification-based sensitivity analysis: application to smoking cessation studies. Clinical Trials. 2010 Jun;7(3):286-98.
2. Norton TR, Lazev AB, Schnoll RA, Miller SM. The impact of email recruitment on our understanding of college smoking. Addict Behav. 2009;34(6-7):531-5.
3. Moloney M, Lazev A, Poole N, Riddell L, Wolfson W. Other medical concerns. In: Our Bodies Ourselves: Menopause. The Boston Women's Health Book Collective. Touchstone, New York. 2006.
4. Gritz ER, Fingeret MC, Vidrine DJ, Lazev AB, Mehta NV, Reece GP. Successes and Failures of the Teachable Moment: Smoking Cessation in Cancer Patients. Cancer. 2006;106:(1)17-27.
5. Vidrine DJ, Arduino RC, Lazev AB, Gritz ER. A randomized trial of a proactive cellular telephone intervention for smokers living with HIV/AIDS. AIDS Care. 2006;20(2):253-60.
6. Lazev AB. National Cancer Institute's Report on Women, Tobacco, & Cancer: An Agenda for the 21st Century Conference - Interventions for Prevention and Treatment Committee Findings.
7. Lazev AB, Vidrine DJ, Arduino RC, Gritz ER. Increasing access to smoking cessation treatment in a low income HIV-positive population: The feasibility of using cellular telephones. Nicotine & Tobacco Research. 2004;6:(2)281-6.
8. Gritz ER, Vidrine DJ, Lazev AB, Amick BC 3rd, Arduino RC. Smoking behavior in a low income multiethnic HIV/AIDS population. Nicotine & Tobacco Research. 2004;6:(1)1-7.
9. Brandon TH, Herzog TA, Juliano LM, Irvin JE, Lazev AB, Nath V. Pretreatment task-persistence predicts smoking cessation outcome. Journal of Abnormal Psychology. 2003;112:(3)448-56.
10. Gritz ER, Lazev AB, Vidrine DJ. Smoking cessation for cancer patients: Bridging the gap between research and treatment. In: Journal of Clinical Oncology Educational Book. American Society of Clinical Oncology. 2003.
11. Gritz ER, Vidrine DJ, Lazev AB. Smoking cessation in cancer patients: Never too late to quit. In: Given B, Given CW, Champion V, Kozachik S, Devoss D, editors. Evidence-Based Cancer Care and Prevention: Behavioral Interventions. New York: Springer Publishers. 2003.
12. Herzog TA, Lazev AB, Irvin JE, Juliano LM, Greenbaum PE, Brandon TH. Testing for group effects during and after treatment: The example of group therapy for smoking cessation. Behavior Therapy. 2002;33:29-43.
13. Brandon TH, Collins BN, Juliano LM, Lazev AB. Preventing relapse among former smokers: A comparison of minimal interventions via telephone and mail. Journal of Consulting and Clinical Psychology. 2000;68:103-13.
14. Lazev AB, Herzog TA, Brandon TH. Classical conditioning of environmental cues to cigarette smoking. Experimental & Clinical Psychopharmacology. 1999;7:56-63.
15. Brandon TH, Lazev AB, Juliano LM. Very delayed smoking relapse warrants research attention. Psychological Reports. 1998;83:72-4.
16. Williams JBW, Spitzer RL, Linzer M, Kroenke K, Hahn SR, deGruy FV, Lazev A. Gender differences in depression in primary care. American Journal of Obstetrics and Gynecology. 1995;173:(2)654-9.
17. Williams JBW, Lazev A. Psychiatric Rating Scales and Psychologic Tests. In Simpson, G. (Ed.), Manual of Psychiatric Disorders. Impact Communications Inc., New York. 1995.

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Developing and Evaluating Interventions to Improve How People Cope with Cancer Risk, Disease, and Survivorship

The goal of our research is to make cancer prevention-control programs more effective by identifying the distinctive ways in which individuals make decisions, adjust to risk information, and manage recommended screening, treatment, follow-up, and prevention regimens. Our efforts focus on the application of assessments and interventions that are specifically targeted and tailored to individual differences among patients and their families. A series of interrelated projects provides a systematic and comprehensive exploration of the psychosocial-biobehavioral links that underlie adaptive responses across the spectrum of cancer risk, disease, and survivorship. The studies in our program are conceptually derived from our integrative theory-based framework, the Cognitive-Social Health Information Processing (C-SHIP) model. This model addresses how different types of individuals process information about cancer threats and prevention-control options, and specifies that behavior is influenced by an individual’s perceived vulnerability to cancer, self-efficacy in dealing with it, expectations about the disease, health values and goals, emotions, and coping strategies. The C-SHIP model also recognizes two main styles of processing cancer risk feedback: high monitoring, which involves scanning for and amplifying threat-related cues; and low monitoring, which involves distracting from such cues and minimizing their impact.

The model enables us to develop both traditional and new technology interventions that help overcome psychosocial barriers to behavioral change, as well as approaches to navigating the health system that help bridge disparities in access to care and thereby contribute to achieving health care quality goals. Based on our model, we are currently exploring decision-making; adherence to recommended screening, prevention, and treatment regimens; adjustment to cancer feedback; biobehavioral linkages from cancer risk through survivorship; and the translation and dissemination of interventions into clinical, community, and other real world service settings. Employing a transdisciplinary team approach, our work focuses particularly on biobehavioral factors in tobacco control; decision making for genetic and biomarker risk feedback, as well as for cancer treatm ent and clinical trial decision making; cancer prevention and control outreach efforts; and psychosocial, behavioral, cognitive, and systems factors in survivorship, as well as in integrated models of survivorship care.

Selected Publications

1. Miller SM, Roussi P, Daly MB, Scarpato J. New Strategies in Ovarian Cancer: Uptake and Experience of Women at High Risk of Ovarian Cancer Who Are Considering Risk-Reducing Salpingo-Oophorectomy. Clin Cancer Res. 2010 Nov;16(21):5094-106.
2. Miller SM, Roussi P. Psycho-oncology 2nd ed. New York, NY: Oxford University Press. Psychosocial issues in cervical cancer screening. Forthcoming 2009.
3. Miller SM, Bowen D J, Croyle RT, Rowland J, editors. Handbook of cancer control and behavioral science: a resource for researchers, practitioners, and policy makers. Washington, DC: American Psychological Association; 2009. 650 p.
4. Miller SM, Bowen DJ, Lyle J, Clark M, Mohr D, Wardle J, Ceballos R, Emmons K, Gritz E, Marlow L. Primary Prevention, Aging, and Cancer: Overview and Future Perspectives. Part of Invited Supplement: Aging in the Context of Cancer Prevention and Control: Perspectives from Behavioral Medicine. Cancer. 2008;Sup 12:3484-92. PubMed
5. Hiatt RA, Miller SM, Vernon SW. Translational research and good behavior. Cancer Epidem Biomar. 2007;16(11):2184-85. PubMed
6. Miller SM, McDaniel S, Rolland J, Feetham S, editors. Individuals, families and the new era of genetics: biopsychosocial perspectives. New York: Norton Publications; 2006. 578 p.

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Research Interests

It is well documented that there are disproportionately higher rates of cancer diagnoses and deaths among Black populations compared to other ethnic groups. This finding is consistent for the Black population in the US as well as developing regions such as the Caribbean and Africa. In addition to socioeconomic factors and access to medical care, environmental exposures, lifestyle and culture are associated with cancer risk. However, the strength of these associations with cancer development may be modified by individual genetic factors.

The ultimate goal of our research program is to use a transdisciplinary approach to address the burden of cancer in Black populations. Through community engagement, we conduct molecular epidemiology research studies in head and neck, lung and prostate cancer by investigating gene x environment interactions that promote racial disparities in cancer.

Through my leadership of the African-Caribbean Cancer Consortium we are able to promote a more holistic approach to better understanding cancer risk and poor outcome among underserved minority populations of African ancestry through research studies conducted locally as well as at a national and global level.

Selected Publications

1. Jackson MD, Tulloch-Reid MK, McFarlane-Anderson N, Watson A, Seers V, Bennett FI, Egleston B, Ragin C. Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness. Genes Nutr. 2012 Sep 25. [Epub ahead of print] PubMed
2. Taioli E, Flores-Obando RE, Agalliu I, Blanchet P, Bunker CH, Ferrell RE, Jackson M, Kidd LC, Kolb S, Lavender NA, McFarlane-Anderson N, Morrison SS, Multigner L, Ostrande EA, Park JY, Patrick AL, Rebbeck TR, Romana M, Stanford JL, Ukoli F, Vancleave TT, Zeigler-Johnson CM, Mutetwa B, Ragin C. Multi-institutional prostate cancer study of genetic susceptibility in populations of African descent. Carcinogenesis 2011 Sept; 32(9):1361-5. PubMed
3. Ragin CC, Langevin SM, Marzouk M, Grandis J, Taioli E. Determinants of head and neck cancer survival by race. Head Neck. 2011 Aug;33(8):1092-8. PubMed
4. Ragin CC, Langevin S, Rubin S, Taioli E. Review of studies on metabolic genes and cancer in populations of African descent. Genet Med. 2010 Jan; 12(1):12-8. PubMed
5. Ragin CC, Taioli E, McFarlane-Anderson N, Avery G, Bennett F, Bovell-Benjamin A, Thompson AB, Carrington A, Campbell-Everett L, Ford J, Hennis A, Jackson M, Lake S, Leske MC, Magai C, Nemesure B, Neugut A, Odedina F, Okobia M, Patrick A, Plummer WB, Reams RR, Roberts R, Scott-Hastings S, Sharma S, Wheeler V, Wu SY, Bunker C. African-Caribbean cancer consortium for the study of viral, genetic and environmental cancer risk factors. Infect Agent Cancer. 2007 Sep 24;2:17. PubMed

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Breast Cancer Research Laboratory

For information about Dr. Russo and her lab, please see the Breast Cancer Research Laboratory website.

Selected Publications

1. Gutierrez PJ, Russo IH, Russo J. Cancer behaviour: an optimal control approach. International J Immunological Studies. 2009;1(1):31-65.
2. Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J. Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol. 2008 Jan;196(1):101-12.
3. Russo J, Russo IH. Hormones and cancer. In: Berstein LM, Santen RJ, editors. Innovative endocrinology of cancer. New York Austin, Tex.: Springer Science+Business Media ; Landes Bioscience; 2008. p. 52-6.
4. Russo J, Russo IH. Breast architecture and the pathogenesis of cancer. In: Pasqualini JR, editor. Breast cancer : prognosis, treatment, and prevention. New York: Informa Healthcare; 2008. p. 1-9.
5. Russo J, Russo IH. Breast development, hormones and cancer. Adv Exp Med Biol. 2008;630:52-6.
6. Russo IH, Russo J. Use of human chorionic gonadotropin in the prevention of breast cancer. Women's Health. 2008;4(1):1-5.
7. Russo J, Balogh GA, Russo IH. Full-term pregnancy induces a specific genomic signature in the human breast. Cancer Epidemiology Biomarkers & Prevention. 2008 Jan;17(1):51-66.
8. Russo J, Russo IH. Breast development, hormones and cancer. In: Innovative Endocrinology of Cancer. Springer-Verlag Berlin; Heidelberger Platz 3, D-14197 Berlin, Germany; 2008. p. 52-6.
9. Moral R, Wang R, Russo IH, Mailo DA, Lamartiniere CA, Russo J. The plasticizer butyl benzyl phthalate induces genomic changes in rat mammary gland after neonatal/prepubertal exposure. BMC Genomics. 2007;8:453.
10. Mello ML, Vidal BC, Russo IH, Lareef MH, Russo J. DNA content and chromatin texture of human breast epithelial cells transformed with 17-beta-estradiol and the estrogen antagonist ICI 182,780 as assessed by image analysis. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis. 2007 Apr;617(1-2):1-7.
11. Russo IH, Russo J. Primary prevention of breast cancer by hormone-induced differentiation. Recent Results Cancer Res. 2007;174:111-30.
12. Russo J, Balogh G, Mailo D, Russo PA, Heulings R, Russo IH. The genomic signature of breast cancer prevention. Recent Results Cancer Res. 2007;174:131-50.
13. Russo J, Balogh G, Russo IH. Breast cancer prevention. Climacteric. 2007 Oct;10 Suppl 2:47-53.
14. Chen JQ, Russo PA, Cooke C, Russo IH, Russo J. ERbeta shifts from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins. Biochim Biophys Acta. 2007 Dec;1773(12):1732-46.
15. Balogh GA, Russo IH, Spittle C, Heulings R, Russo J. Immune-surveillance and programmed cell death-related genes are significantly overexpressed in the normal breast epithelium of postmenopausal parous women. Int J Oncol. 2007 Aug;31(2):303-12.
16. Balogh GA, Russo J, Mailo DA, Heulings R, Russo PA, Morrison P, Sheriff F, Russo IH. The breast of parous women without cancer has a different genomic profile compared to those with cancer. Int J Oncol. 2007 Nov;31(5):1165-75.
17. Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, Moral R, Russo J. Genomic signature induced by pregnancy in the human breast. Int J Oncol. 2006;28(2):399-410.
18. Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, Garber J, Russo IH. 17-beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. The FASEB J. 2006;20:1622-34.
19. Fernandez, S.V., Russo, I.H., Russo, J. Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells. Int J Cancer, 118:1862-1868, 2006.
20. Russo J, Balogh GA, Chen JQ, Fernandez SV, Fernbaugh R, Heulings R, Mailo DA, Moral R, Russo PA, Sheriff F, Vanegas JE, Wang R, Russo IH. The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci. 2006 Jan 1;11:151-72.
21. Russo J, Balogh GA, Heulings R, Mailo DA, Moral R, Russo PA, Sheriff F, Vanegas J, Russo IH. Molecular basis of pregnancy-induced breast cancer protection. Eur J Cancer Prev. 2006 Aug;15(4):306-42.
22. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):89-96.
23. Russo J, Santen RJ, Russo IH. Hormonal control of the breast development. In: DeGroot LJ, Jameson JL, editors. Endocrinology. Philadelphia, PA: W.B. Saunders Co.; 2005. p. 3045-55.
24. Chen J, Contreras R, Wang R, Fernandez S, Shoshani L, Russo I, Cereijido M, Russo J. Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs?. Breast Cancer Res Treat. 2005 Dec;eFIRST date:2.
25. Fernandez SV, Russo IH, Lareef M, Balsara B, Russo J. Comparative genomic hybridization of human breast epithelial cells transformed by estrogen and its metabolites. Int J Oncol. 2005 Mar;26(3):691-5.
26. Lareef MH, Garber J, Russo PA, Russo IH, Heulings R, Russo J. The estrogen antagonist ICI-182-780 does not inhibit the transformation phenotypes induced by 17-beta-estradiol and 4-OH estradiol in human breast epithelial cells. Int J Oncol. 2005 Feb;26(2):423-9.
27. Meyer JS, Alvarez C, Milikowski C, Olson N, Russo I, Russo J, Glass A, Zehnbauer BA, Lister K, Parwaresch RG. Breast carcinoma malignancy grading by Bloom-Richardson system vs proliferation index: reproducibility of grade and advantages of proliferation index. Mod Pathol. 2005 Aug;18(8):1067-78.
28. Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, Russo IH. Breast differentiation and its implication in cancer prevention. Clin Cancer Res. 2005 Part 2 Suppl. S JAN 15;11(2):931S-936S.
29. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Research. 2005;7(3):131-42.
30. Balogh GA, Russo IH, Russo J. Truncation of the mismatch repair protein PMS2 during the neoplastic transformation of human breast epithelial cells in vitro. Int J Oncol. 2004 Aug;25(2):381-7.
31. Guo SC, Russo IH, Lareef MH, Russo J. Effect of human chorionic gonadotropin in the gene expression profile of MCF-7 cells. Int J Oncol. 2004 Feb;24(2):399-407.
32. Lareef MH, Tahin Q, Song J, Russo IH, Mihaila D, Slater CM, Balsara B, Testa JR, Broccoli D, Grobelny JV, Mor G, Cuthbert A, Russo J. Chromosome 17p13.2 transfer reverts transformation phenotypes and Fas-mediated apoptosis in breast epithelial cells. Mol Carcinog. 2004 Apr;39(4):234-46.
33. Russo J, Russo IH. Genotoxicity of steroidal estrogens. Trends in Endocrinology and Metabolism. 2004 Jul;15(5):211-4.
Russo, J., Russo, I.H. A new paradigm in breast cancer prevention. Med. Hypotheses Res. 1:11-22, 2004.
34. Russo J, Russo IH. Development of the human breast. Maturitas. 2004 Sep 24;49(1):2-15.
35. Balogh GA, Russo IH, Russo J. Mutations in mismatch repair genes are involved in the neoplastic transformation of human breast epithelial cells. Int J Oncol. 2003 Aug;23(2):411-9.
36. Guo SC, Russo IH, Russo J. Difference in gene expression profile in breast epithelial cells from women with different reproductive history. Int J Oncol. 2003 Oct;23(4):933-41.
37. Lanza-Jacoby S, Miller S, Flynn J, Gallatig K, Daskalakis C, Masferrer JL, Zweifel BS, Sembhi H, Russo IH. The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in HER-2/neu mice. Cancer Epidemiology Biomarkers & Prevention. 2003 Dec;12(12):1486-91.
38. Russo J, Russo IH. (Editors) Biological and Molecular Basis of Breast Cancer. Springer-Verlag, Heidelberg, Germany, 2003.
39. Russo J, Lareef AH, Balogh G, Guo S, Russo IH. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J Steroid Biochem Mol Biol. 2003 Oct;87(1):1-25.
40. Blumenstein R, Dias M, Russo IH, Tahin Q, Russo J. DNA content and cell number determination in microdissected samples of breast carcinoma in situ. Int J Oncol. 2002 Aug;21(2):447-50.
41. Jiang X, Russo IH, Russo J. Alternately spliced luteinizing hormone/human chorionic gonadotropin receptor mRNA in human breast epithelial cells. Int J Oncol. 2002 Apr;20(4):735-8.
42. Jiang X, Russo IH, Russo J. Human chorionic gonadotropin and inhibin induce histone acetylation in human breast epithelial cells. Int J Oncol. 2002 Jan;20(1):77-9.
43. Russo IH. Cigarette smoking and risk of breast cancer in women. Lancet. 2002 Oct 5;360(9339):1033-4.
44. Russo J, Lareef MH, Tahin Q, Hu YF, Slater C, Ao X, Russo IH. 17Beta-estradiol is carcinogenic in human breast epithelial cells. J Steroid Biochem Mol Biol. 2002 Feb;80(2):149-62.
45. Russo J, Tahin Q, Lareef MH, Hu YF, Russo IH. Neoplastic transformation of human breast epithelial cells by estrogens and chemical carcinogens. Environ Mol Mutagen. 2002;39(2-3):254-63.
46. Soler AP, Russo J, Russo IH, Knudsen KA. Soluble fragment of P-cadherin adhesion protein found in human milk. J Cell Biochem. 2002;85(1):180-4.
47. Jiang X, Russo IH, Russo J. Human chorionic gonadotropin and inhibin induce histone acetylation in human breast cancer cells. Int J Oncol. 2001;19:1-3.
48. Russo J, Hu YF, Silva ID, Russo IH. Cancer risk related to mammary gland structure and development. Microsc Res Tech. 2001 Jan 15;52(2):204-23.
49. Russo J, Hu YF, Tahin Q, Mihaila D, Slater C, Lareef MH, Russo IH. Carcinogenicity of estrogens in human breast epithelial cells. APMIS. 2001 Jan;109(1):39-52.
50. Russo J, Russo IH. The pathway of neoplastic transformation. Radiat Res. 2001;155:151-4.
51. Russo J, Santen R, Russo IH. Hormonal control of the breast development. In Endocrinology, Fourth Edition, edited by LJ DeGroot, JL Jameson. WB Saunders Company, Philadelphia, Vol.3, pp.2181-8. 2001
52. Russo J, Lynch H, Russo IH. Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer. Breast J. 2001 Sep-Oct;7(5):278-91.
53. Russo IH, Tahin Q, Huang Y, Russo J. Cellular and molecular changes induced by the chemical carcinogen benz(a)pyrene in human breast epithelial cells in association with smoking and breast cancer. Journal of Womens Cancer. 2001;3:29-36.

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Research Interests

Our research focuses on the innovative use of quantitative methods and information technology in cancer research. Our statistical methodology research includes development and application of novel methods for the analysis of correlated failure time and high throughput laboratory data. We are also interested in the creation of new randomized Phase II clinical trial designs that permit early stopping in both patient number and time of initial evaluation. These designs provide for early termination for futility or efficacy, and should be particularly appropriate for studies in patient populations with a high likelihood for rapid disease progression. Our collaborations with numerous investigators conducting clinical, translational, cancer control, epidemiology, and basic science research rigorously extend the quantitative interpretation of results from these disciplines. Our informatics research facilitates cancer investigations by promoting the use of computer-based methods that improve research efficiency and data quality. Special areas of interest include large-scale data integration, and the development and application of web-based technologies to enable remote data collection/presentation, health education and new interventions.  

Selected Publications

1. Bondy ML, Lustbader ED, Halabi S, Ross E, Vogel VG. Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst. 1994 Apr 20;86(8):620-5. PubMed
2. Ross EA, Moore D. Modeling clustered, discrete or grouped-time survival data with covariates. Biometrics. 1999 Sep;55(3):813-9. PubMed
3. Evans AA, Chen G, Ross EA, Shen FM, Lin WY, London WT. Eight year follow-up of the 90,000 person Haimen City Cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):369-76. PubMed
4. Schilder RJ, Pathak HB, Lokshin AE, Holloway RW, Alvarez RD, Aghajanian C, Min H, Devarajan K, Ross E, Drescher CW, Godwin AK. Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash. Gynecol Oncol. 2009 Apr;113(1):21-7. PubMed
5. Bellacosa A, Godwin AK, Peri S, Devarajan K, Caretti E, Vanderveer L, Bove B, Slater C, Zhou Y, Daly M, Howard S, Campbell KS, Nicolas E, Yeung AT, Clapper ML, Crowell JA, Lynch HT, Ross E, Kopelovich L, Knudson AG. Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations. Cancer Prev Res (Phila). 2010 Jan;3(1):48-61. PubMed
6. Ariazi, E.A., Cunliffe, H., Lewis-Wambi, J., Slifker, S., Willis, A., Ramos, P., Tapia, P., Kim, H., Yerrum, S., Sharma, C., Nicolas, E., Balagurunathan, Y., Ross, E.A., Jordan, V.C., Estrogen-induces apoptosis in estrogen deprivation-resistant breast cancer via stress responses as identified by global gene expression. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):18879-86. PubMed

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Breast Cancer Research Laboratory

For information about Dr. Russo and his lab, please see the Breast Cancer Research Laboratory website.

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Behavioral Science Research

Many patients experience cognitive difficulties, including problems with attention, concentration, and memory at some point following a cancer diagnosis.  Several factors contribute to these changes in cognitive function. For example, fatigue, feeling stressed or anxious, and hormonal changes can each impact cognitive function. Specific cancer treatments may also be associated with cognitive changes.  My research has been funded by the Department of Defense and National Cancer Institute and focuses on understanding the causes of cancer-related cognitive change and the impact of these cognitive difficulties on quality of life.  My goal is to implement a systematic program of research examining psychosocial, biological, and clinical factors that contribute to adverse changes in cognitive function, and to develop interventions to improve cognitive outcomes and quality of life for patients and survivors.

Related Areas of Research Interest
Stress, Coping and Cognitive Function
Cognition and Emotion
Survivor Quality of Life
Young Adult Survivorship
Peer-support

Selected Publications

1. Shapiro, PJ. Cancer brain fog. Coping with Cancer Magazine, 2010;24(3), 8. http://copingmag.com/cwc/index.php/feature_article/cancer_brain_fog/
2. Lai J, Butt Z, Wagner L, Sweet J, Beaumont L, Vardy J, Jacobsen P, Shapiro PJ, Jacobs S, Cella D. Evaluating the dimensionality of perceived cognitive function: An illustration using the Functional Assessment of Cancer Therapy – Cognitive Function (FACT-Cog). Journal of Pain and Symptom Management. 2009;37:982-95. PubMed
3. Kenen RH, Shapiro PJ, Friedman S, Hansoo L, Coyne JC. Women with BRCA1/2 mutations renegotiating a post-prophylactic mastectomy identity: Self-image and self-disclosure. Journal of Genetic Counseling, 2007;16:789–98. PubMed
4. Kenen RH, Shapiro PJ, Friedman S, Coyne JC. Peer-support in coping with medical uncertainty: Discussion of prophylactic oophorectomy and hormone replacement therapy on a web-based message board. Psycho-Oncology, 2007;16:763-71. PubMed
5. Shapiro PJ, Jacobs LA, Palmer SC, Coyne JC, Meadows AT, Vaughn DJ. Neurocognitive function in long-term survivors of testicular cancer. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings. 23 (Suppl. 16), 8034. 2005. JCO
6. Coyne JC, Palmer SC, Shapiro PJ. Prescribing antidepressants to advanced cancer patients with mild depressive symptoms is not justified: Response to Fisch et al. Journal of Clinical Oncology. 2004;22:205-6. PubMed
7. Coyne JC, Palmer SC, Shapiro PJ, Thompson, R. Distress, psychiatric morbidity, and prescriptions for psychotropic medication in a breast cancer waiting room sample. General Hospital Psychiatry. 2004;26,121-8. PubMed
8. Shapiro PJ, Coyne JC, Kruus LK, Palmer SC, Malkowicz SB, Vaughn DJ. Interest in services among prostate cancer patients receiving androgen deprivation therapy. Psycho-Oncology, 2004;13:512-25. PubMed
9. Sullivan PA, Shapiro PJ, Thompson R. Psychological reactions to terrorist attacks: Response to Schlenger et al. Journal of the American Medical Association, 288, 2684. 2002. PubMed
10. Shapiro PJ, Weisberg RW. Positive affect and creativity: Symptom of psychopathology or component of creative process? Bulletin of Psychology and the Arts. 2000;1:58-61.
11. Shapiro PJ, Weisberg RW. Creativity and bipolar diathesis: Common behavioural and cognitive components. Cognition and Emotion, 1999;13:741-62.

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Research Interests

Dr. Wen is an Assistant Professor in the Cancer Prevention and Control program. Her major interests draw on her background in systems engineering, health communication, behavioral and decision science, and information technology to develop and evaluate effective tools and solutions to help individuals and organizations manage and deal with health-related challenges.

She is currently working within the Intervention Development and Measurement Core on a NCI-funded Cancer Information Service Research Consortium program project to develop three interactive multimedia programs to assist prostate and breast patients through their cancer diagnosis and breast cancer patients following completion of their treatment. Funded by CCK foundation, she is also conducting an overseas study that examines the needs and experience of breast cancer patients and develops a narrative communication intervention to facilitate treatment decision making and adaptive coping for breast cancer patients in Taiwan. In 2011, Dr. Wen has received a 5-year Agency for Healthcare Research and Quality K01 Career award to develop, implement, and evaluate an electronic patient portal that will integrate patient-accessible electronic medical records, evidence-based educational and psychosocial content, clinical- and peer- communication in a comprehensive format to empower breast cancer patients and facilitate their treatment decision making and care management. Funded by the Asian Community Cancer Health Disparities Center (U54) at Temple University, Dr. Wen is conducting a pilot study using a mixed-methods approach and community-based participatory research principles to examine the survivorship needs and experience of Chinese American breast cancer patients at the states of Pennsylvania and New York.

Selected Publications

1. Boberg, E, Gustafson, D., Hawkins, R., Offord, K., Koch, C., Wen, K.Y., Kreutz, K., and Salner, A.(2003) Assessing the Unmet Information, Support and Care Delivery Needs of Men with Prostate Cancer. Patient Education and Counseling 49: 233-242.
2. Wen, K.Y. and Gustafson, D. (2004) Needs Assessment for Cancer Patients and Their Families. Health and Quality of Life Outcomes 2:11.
3. Gustafson, D. and Wen, K.Y. (2007). Implementation Model Development and Testing. In Gustafson, D., Brennan, P. & Hawkins, R. (Eds.). Investing in eHealth: What It Takes to Sustain Consumer Health Informatics. Springer New York.
4. Bernard, L.L., Wen, K.Y., Gustafson, D. H., Guarnaccia, C. A., Cleary, J.F., Dinauer, S.K., and McTavish, F. M. (2008) Caregivers’ Differing Needs Across Key Experiences of the Advanced Cancer Disease Trajectory. Palliative and Supportive Care. 6(3):265-72. PMID: 18662420.
5. Wen, K.Y., Gustafson, D.H., Hawkins, R.P., Brennan, P.F., Dinauer, S., Johnson, P.R., and Siegler, T. (2010) Developing and validating a model to predict the success of an IHCS implementation: the Readiness for Implementation Model. Journal of the American Medical Informatics Association. 17(6): p. 707-713. PMID: 20962135.
6. Wen, K.Y., Kreps, G., Zhu, F., and Miller, S. Consumer’s perceptions about and use of the Internet for personal health records and health information exchange: Analysis of the 2007 Health Information National Trends Survey (2010). Journal of Medical Internet Research. 12(4):e73. PMID: 21169163.
7. Wen, K.Y., McTavish, F., Kreps, G., Wise, M., and Gustafson, D. (2011) From Diagnosis to Death: A Case Study of Coping with Breast Cancer as Seen through Online Discussion Group Messages. Journal of Computer Mediated Communication. 16(2): 331-361.
8. Roussi, P., Sherman, S. A., Miller, S.M., Hurley, K., Daly, M.B., Godwin, A., Buzaglo, and Wen, K.Y. (2011). Identification of cognitive profiles among women considering BRCA1/2 testing through the utilization of cluster analytic techniques. Psychology and Health. 26(10):1327-43. PMID: 21756124.
9. Wen, K.Y., Miller, S., Lazev, A., and Zhu, F. (2012) Predictors of smoking cessation treatment adherence in a socioeconomically disadvantaged sample of pregnant women. Journal of Health Care for the Poor and Underserved. 23(3): 1222-1238.
10. Wen, K.Y., Miller, S., Stanton, A., Fleisher, L., Morra, M., Jorden, A., Diefenbach, M., Ropka, M. and Marcus, A. (2012). The Development and Preliminary Testing of a Multimedia Patient-Provider Survivorship Communication Module for Breast Cancer Survivors. Patient Education and Counseling. 88(2): 344-9. PMID: 22770812.
11. Fleisher, L., Miller, S., Crookes, D., Kandadai, V., Wen, K.Y., Slamon, R., Berger, T., and Chaivous, J. (2012). Implementation of a Theory-based, Non-clinical Patient Navigator Program to Address Barriers in an Urban Cancer Center Setting. Journal of Oncology Navigation & Survivorship. June 3(3).

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Research Interests

Advances in translational research have led to new and promising treatments for patients with localized and advanced cancers. My research focuses on the utilization of these new treatments and what factors may influence patient choices.  While these therapies provide hope for patients with serious illnesses, many can be costly for both individual patients and society.  In addition, treatments can be associated with toxicities which may be mild for some but unacceptable for others.  I am interested in understanding how to best utilize these new treatment to utilize these resources is a manner which optimizes treatment outcomes.

My research interests are based on my experiences as a medical oncologist. Our role is to discuss available treatments and help them arrive at a decision that best suits their suits their preferences. As an active clinical investigator, I participate in trials of new agents for patients with advanced urothelial, prostate and renal cell cancers.  I encourage my patients to participate in these studies, which allow us to understand the both the benefits and risks of new treatments.   I am also interested in using large administrative datasets to answer questions that cannot be answered in traditional clinical trials.  

Selected Publications

1. Wong Y, Hamilton O, Egleston B, Salador K, Murphy C, Meropol NJ. Understanding how out of pocket expenses, treatment value and patient characteristics influence treatment choices. The Oncologist. 2010;15(6):566-76.
2. Kutikov A, Egleston BL, Wong YN, Uzzo RG, Evaluating Overall Survival and Competing Risks of Death in Patients with Localized Renal Cell Carcinoma Using a Comprehensive Nomogram. Journal of Clinical Oncology. 2010 Jan 10;28(2):311-7.
3. Earle CC, Weiser MR, Shibata S, Skibber JM, Wilson J, Rajput A, Wong Y, Romanus DK, TerVeer A, Schrag S,Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in stage II colon cancer. Journal of Surgical Oncology. 2009 Dec 1;100(7):525-8.
4. Wong, Y, Freedland SJ, Egleston B, Vapiwala N, Uzzo RG, Armstrong K, The Role of Primary Androgen Deprivation Therapy in Localized Prostate Cancer. European Urology. 2009 Oct: 56(4): 609-16.
5. Putt M, Long JA, Montagnet C, Silber JH, Chang VW, Liao KJ, Schwartz JS, Pollack CE, Wong YN, Armstrong K Racial Differences in the Impact of Comorbidities on Survival among Elderly Men with Prostate Cancer. Medical Care Research Review. 2009 Aug;66(4):409-35.
6. Wong YN, Speier, W, Meropol NJ, Sargent D, Goldberg RM, Beck JR, Cost Implications of New Treatments for Colorectal Cancer. Cancer. 2009 May 15;115(10):2081-91.
7. Egleston B, Wong Y, Sensitivity analysis to investigate the impact of a missing covariate on survival analyses using cancer registry data. Statistics in Medicine. 2009, Feb 23;28(10):1498-1511.
8. Scoll BJ, Wong YN, Egleston B, Kunkle DA, Saad IR, Uzzo RG Age, Tumor Size, and Relative Survival in Localized Renal Cell Carcinoma. Journal of Urology. 2009 Feb 181(2):506.
9. Wong Y, Freedland SJ, Egleston BL, Hudes GR , Schwartz JS, Armstrong K. The Role of Androgen Deprivation Therapy in Node Positive Prostate Cancer.” Journal of Clinical Oncology. 2009 Jan 1;27(1):100-5.
10. Hassett, MJ, Hughes ME, Niland JC, Edge SB, Theriault RL, Wong Y, Wilson J, Carter WB, Blayney, DW, Weeks JC, Chemotherapy use for hormone receptor positive, lymph node negative breast cancer, Journal of Clinical Oncology. 2008 Dec 1;26(34):5553-60.
11. Litwin, S, Wong Y, Hudes G. Early Stopping Designs Based on Progression Free Survival at an Early Time Point in the Initial Cohort. Statistics in Medicine. 2007 Oct 30;26(24):4400-15.
12. Wong Y, Mitra N, Hudes G, Localio, R, Schwartz JS, Wan F, Montagnet C, Armstrong K. Survival Associated with Treatment vs. Observation of Localized Prostate Cancer in Elderly Men. JAMA 2006. Dec 13;296(22):2683-93.
13. Massaro T, Wong Y. Positive Experiences with Medical Savings Accounts in Singapore. Health Affairs 1995. Summer;14(2):267-72.

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Antibody-Based Therapy and Detection of Cancer

Our research is focused upon optimizing and exploiting engineered antibody fragments to both detect and treat solid tumors. To accomplish this, we are using phage display and hybridoma technology to develop new antibodies specific for novel tumor antigens. We are using the antibodies that successfully target tumors in vivo in an unconjugated form to directly inhibit tumor growth or employing them as vehicles for the delivery of cytotoxic agents that can kill the tumor cells or positron-emitting radioisotopes to facilitate ImmunoPET tumor detection. We are also employing our engineered antibodies as the basis for nano and micro biosensors for the detection of tumor biomarkers and pathogens in biologic fluids. Additionally, we are examining the impact of antibody affinity and avidity on tumor targeting and penetration, particularly in the setting of background expression of the target antigen on normal tissue.

Selected Publications

1. Rudnick SI and Adams, GP. Affinity and Avidity in Antibody-Based Tumor Targeting. Cancer Biotherapy and Radiopharmaceuticals 2009, 2:155-61. PubMed
2. Robinson MK, Hodge KM, Horak E, Sundberg AL, Russeva M, Shaller CC, von Mehren M, Shchaveleva I, Simmons HH, Marks JD, Adams GP. Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. Br J Cancer. 2008 Oct;99(9):1415-25. PubMed
3. Capobianco JA, Shih WY, Yuan Q-A, Adams GP, Shih W-H. Label-free, all-electrical, in situ human epidermal growth receptor 2 detection Review of Scientific Instruments. 2008;79:076101-3. PubMed
4. Yuan QA, Robinson MK, Simmons HH, Russeva M, Adams GP. Isolation of anti-MISIIR scFv molecules from a phage display library by cell sorter biopanning. Cancer Immunol Immunother. 2008 Mar;57(3):367-78. PubMed
5. Robinson MK, Shaller C, Garmestani K, Plascjak PS, Hodge KM, Yuan QA, Marks JD, Waldmann TA, Brechbiel MW, Adams GP. Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies. Clin Cancer Res. 2008 Feb 1;14(3):875-82. PubMed
6. Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nature Biotechnol. 2005;23:1147-57. Review. PubMed
7. Robinson MK, Doss M, Shaller C, Narayanan D, Marks JD, Adler LP, Gonzalez Trotter DE, Adams GP. Quantitative immuno-positron emission tomography imaging of HER2-positive tumor xenografts with an iodine-124 labeled anti-HER2 diabody. Cancer Research. 2005;65:1471-8. PubMed
8. Adams GP, Schier R, McCall AM, Simmons H, Horak E, Alpaugh RK, Marks JD, Weiner LM. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Research. 2001;61:4750-5. PubMed

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Treatment Choices Defined by Molecular Profile

The main focus of my research is to improve targeted therapy for cancer, and to develop new rational strategies for combination of targeted agents. In the clinic, epidermal growth factor receptor (EGFR)-targeting antibodies or small kinase inhibitor molecules are widely used to treat patients with gastrointestinal (GI), breast, head and neck, and lung cancers. Unfortunately, the clinical efficacy of these agents is limited by intrinsic primary and acquired resistance factors. Our lab has initially focused on development of new treatment strategies utilizing a systematic synthetic lethal screening approach to identify new signaling proteins that can be blocked simultaneously with EGFR, to improve the anti-cancer activity of EGFR-targeting drugs. We have identified a number of potential therapeutically exploitable targets have been identified (Astsaturov I. et al., Science Signaling (2010)), and ongoing work in the lab assessed their mode of action. Besides testing novel signaling mechanisms in the laboratory, we also are using the research data to generate concepts for testing in the clinical trials. One such clinical trial is ongoing (Vandetanib [a vascular endothelial growth factor receptor (VEGFR) inhibitor] in combination with chemotherapy and radiation for patients with operable esophageal cancer), and several more are in the late stages of preparation.

Selected Publications

1. Astsaturov I, Ratushny V, Sukhanova A, Einarson MB, Bagnyukova T, Zhou Y, Devarajan K, Silverman JS, Tikhmyanova N, Skobeleva N, Pecherskaya A, Nasto RE, Sharma C, Jablonski SA, Serebriiskii IG, Weiner LM, Golemis EA. Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies. Sci Signal. 2010 Sep 21;3(140):ra67. PMID: 20858866. PubMed
2. Chun YS, Milestone BN, Watson JC, Cohen SJ, Burtness B, Engstrom PF, Haluszka O, Tokar JL, Hall MJ, Denlinger CS, Astsaturov I, Hoffman JP. Defining Venous Involvement in Borderline Resectable Pancreatic Cancer. Ann Surg Oncol. 2010 Aug 20. PMID: 20725860. PubMed
3. Astsaturov IA, Meropol NJ, Alpaugh RK, Burtness BA, Cheng JD, McLaughlin S, Rogatko A, Xu Z, Watson JC, Weiner LM, Cohen SJ. Phase II and Coagulation Cascade Biomarker Study of Bevacizumab With or Without Docetaxel in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma. Am J Clin Oncol. 2010 May 7. PMID: 20458210. PubMed
4. Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009 Aug;21(8):1255-68. Epub 2009 Mar 1. Review. PMID: 19258037. PubMed
5. Hopper-Borge EA, Nasto RE, Ratushny V, Weiner LM, Golemis EA, Astsaturov I. Mechanisms of tumor resistance to EGFR-targeted therapies. Expert Opin Ther Targets. 2009 Mar;13(3):339-62. Review. PMID: 19236156. PubMed

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Research Interests

My laboratory is interested in immunotherapy for cancer, with particular emphasis on the clinical development and application of monoclonal antibodies. Recent work from my group includes a Phase I trial of naptumomab estafenatox, a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to the antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T. In addition to developing new monoclonal antibodies, I am conducting clinical trials exploring the immunological responses that occur as a result of cetuximab therapy-associated antibody-dependent cellular cytotoxicity (ADCC)ADCC, with the goal of augmenting these immune responses to achieve improved efficacy of antibody therapy. In addition, I am involved in a number of clinical trials with various other monoclonal antibodies such as cetuximab. My latest lung cancer trial explores the relationship between EGFR and Aurora Kinase in lung cancer.

Selected Publications

1. Binyamin L, Alpaugh RK, Campbell KS, Borghaei H, Weiner LM. Rituximab-mediated ADCC is augmented by concomitant interference with inhibitory self-recognition by human NK cells. Blood. 2005;106:690A-691A.
2. Borghaei H, Alpaugh K, Hedlund G, Forsberg G, Langer C, Rogatko A, Hawkins R, Dueland S, Lassen U, Cohen RB. Phase I dose escalation, pharmacokinetic and pharmacodynamic study of naptumomab estafenatox alone in patients with advanced cancer and with docetaxel in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:4116-23.
3. Borghaei H, Alpaugh RK, Bernardo P, Palazzo IE, Dutcher JP, Venkatraj U, Wood WC, Goldstein L, Weiner LM. Induction of adaptive Anti-HER2/neu immune responses in a Phase 1B/2 trial of 2B1 bispecific murine monoclonal antibody in metastatic breast cancer (E3194): A Trial Coordinated by the Eastern Cooperative Oncology Group. J Immunother. 2007;30:455-467.
4. Borghaei H, Binyamin L, Astsaturov I, Weiner AM. Antibody therapy of cancer. In: Molecular Targeting in Oncology. (Kaufman, H.L., Wadler, S., Antman, K., eds.), pp. 371-412. Humana Press, Totowa, NJ, 2008. Book Chapter
5. Borghaei H, Langer CJ, Millenson M, Ruth KJ, Litwin S, Tuttle H, Seldomridge JS, Rovito M, Mintzer D, Cohen R, Treat J. Phase II study of paclitaxel, carboplatin, and cetuximab as first line treatment, for patients with advanced non-small cell lung cancer (NSCLC): results of OPN-017. J Thorac Oncol. 2008;3:1286-1292.
6. Borghaei H, Mehra, R., Simon, G. Current issues in adjuvant chemotherapy for resected, stage IB non-small-cell lung cancer. Fut Oncol. 2009;5:19-22.
7. Borghaei H, Robinson MK, Weiner LM. Monoclonal antibody therapy of cancer. In: Immunotherapy of Cancer (Disis, M.L., ed.), pp. 487-502. Humana Press, Totowa, NJ, 2006.
8. Borghaei H Smith MR, Campbell KS. Immunotherapy of cancer. Eu J Pharmacol. 2009;625:41-54.
9. Carcereny E, Moran T, Felip E, Borghaei H, Fitzgerald T, Clark J, Guan S, Hsu K, Beckman R, Yan L, Rosell R, Johnson DH. An open label, randomized Phase I/IIA Trial evaluating MK-0646, an anti-IGF-1R monoclonal antibody (MoAB), in combination with erlotinib for patients with recurrent non-small cell lung cancer (NSCLC). 13th World Conference on Lung Cancer, San Francisco, July, 2009. Conference
10. Faller BA, Robu VG, Borghaei H. Therapy-related acute myelogenous leukemia with an 11q23/MLL translocation following adjuvant cisplatin and vinorelbine for non-small-cell lung cancer. Clin Lung Cancer. 2009;10:438-440.
11. Huang C, Treat J, Borghaei H, Millenson MM, Mintzer DM, Cohen RB, Staddon AP, Seldomridge J, Langer CJ. Promising survival in patients with recurrent non small cell lung cancer (NSCLC) treated with docetaxel and gemcitabine in combination as second line therapy. J Thorac Oncol. 2008;3:1032-1038. Not supported by NIH funding
12. Kurzrock R, Fayad L, Voorhees P, Furman RR, Lonial S, Borghaei H, Jagannath S, Sokol L, Cornfeld M, Qi M, Jiao T, Herring J, Qin X, van Rhee F. A Phase I study of CNTO 328, an anti-interelukin-6 monoclonal antibody in patients with A-cell non-hodgkin's lymphoma, multiple myeloma, or Castleman's disease, pp. 371-372, 2008. Book Chapter
13. Narra K, Borghaei H, Al-Saleem T, Hoeglund M, Smith MR. Pure red cell aplasia in B-cell lymphoproliferative disorder treated with rituximab: Report of two cases and review of the literature. Leuk. Res. 2005;30:109-114.
14. Robinson MK, Borghaei H, Adams GP, Weiner LM. Pharmacology of cancer biotherapeutics – monoclonal antibodies. In: Cancer: Principles and Practice of Oncology (DeVita, V.T., Hellman, S., Rosenberg, S.A., eds.), pp. 537-547. Lippincott Williams & Wilkins, 2008. Book Chapter
15. Shafer D, Borghaei H, Millenson M, Nicolaou N, Al-Saleem TI, Leasure NC, Padavic K, Smith MR, Schilder RJ. Vinblastine, mitoxantrone and prednisone (MVP) followed by involved field radiotherapy (IF-XRT) for early clinical stage Hodgkins's lymphoma: Long term follow-up. Blood. 2005;106:751A-751A.
16. Shafer, D., Smith, M.R., Litwin, S., Li, T., Borghaei H, Al-Saleem, T.I. Peripheral blood CD3(+)CD4(+) and CD3(-)CD56(+) cell counts and circulating lymphoma cells are significant predictors of overall survival in newly diagnosed follicular lymphoma. Blood. 2007;110:767A-768A.
17. Shafer D, Wu H, Al-Saleem T, Reddy K, Borghaei H, Lessin S, Smith M. Cutaneous precursor B-cell lymphoblastic lymphoma in 2 adult patients: clinicopathologic and molecular cytogenetic studies with a review of the literature. Arch Dermatol. 2008 Sep;144(9):1155-62. Accepted prior to April 7, 2008
18. Smith M, Borghaei H. Comment on Phase II study of weekly low-dose paclitaxel for relapsed and refractory non-Hodgkin's lymphoma: A Wisconsin Oncology Network Study, by Kahl et al., Cancer Invest. 2005;23:13-18.
19. Smith MR, Borghaei H. Comment on phase II study of weekly low-dose paclitaxel for relapsed and refractory non-Hodgkin's lymphoma: A Wisconsin Oncology Network Study," by Kahl et al. Cancer Invest. 200523:572.
20. Weiner LM, Borghaei H. Targeted therapies in solid tumors: Monoclonal antibodies and small molecules. Hum Antibodies. 2006;15:103-111.

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Research Interests

Dr. Burtness is a co-leader of the Keystone Program in Head and Neck Cancer. Her studies of EGFR-directed therapies are directed at personalizing optimal treatments for patients based on the clinical features of their cancer. She is an accomplished clinical investigator with specific expertise in the treatment of head and neck, esophageal, pancreatic and colorectal cancers. She has shown that high EGFR expression predicted resistance to cetuximab in head and neck cancers. She chairs an investigator-initiated phase I study of cetuximab with escalating doses of the mTOR inhibitor everolimus to target signaling from pAkt, and an investigator-initiated phase II trial in head and neck cancer of chemotherapy plus cetuximab, followed by addition of erlotinib to target nuclear EGFR and enhance inhibition of membrane-bound EGFR.

As Chair of the Head and Neck Committee in the Eastern Cooperative Oncology Group and a member of the NCI Head and Neck Steering Committee, she helps shape the national agenda for research on all stages of head and neck cancer.

Selected Publications

1. Chung C, Seeley E, Roder H, Grigorieva J, Tsypin M, Roder J, Burtness B, Argiris A, Forastiere A, Gilbert J, Murphy B, Caprioli R, Carbone D, Cohen E. Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2010;19:35865.
2. Turaka A, Li T, Yu JQ, Nicolaou N, Burtness B, Lango MN, Ridge JA, Feigenberg SJ. Intensity Modulated Radiation Therapy (IMRT) for Thyroid Cancer. Thyroid Sci. 2010;5:CLS1-5.
3. Chun, YS, Milestone BN, Watson JC, Cohen SJ, Burtness B, Haluszka O, Tokar JL, Hall MJ, Denlinger CS, Dushkin H, Astsaturov I, Kuritzky NK, Hoffman JP. Defining venous involvement in borderline resectable pancreatic cancer. Ann Surg Oncol. 2010 Nov;17(11):2832-8.
4. Rusthoven KE, Feigenberg, SJ, Raben D, Kane M, Song JI, Nicolaou N, Mehra R, Burtness B, Ridge J, Swing R, Lango M, Cohen R, Jimeno A, Chen C. Initial results of a phase I dose-escalation trial of concurrent and maintenance erlotinib and reirradiation for recurrent and new primary head and neck cancer. Int J Radiation. Oncol Biol Phys. 2010;78:1020-5.
5. Pectasides E, Egloff AM, Sasaki C, Kountourakis P, Burtness B, Fountzilas G, Dafni U, Zaramboukas T, Rampias T, Rimm D, Grandis J, Psyrri A. Nuclear Localization of Signal Transducer and Activator of Transcription 3 in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis. Clin Cancer Res. 2010;16:2427-34.
6. Turaka A, Li T, Nicolaou N, Lango MN, Burtness B, Horwitz EM, Ridge JA, Feigenberg SJ. Use of a Conventional Low Neck Field (LNF) and Intensity-Modulated Radiotherapy (IMRT): No Clinical Detriment of IMRT to an Anterior LNF During the Treatment of Head-and Neck-Cancer. Int J Radiat Oncol Biol Phys. 2010 Apr 10. [Epub ahead of print].
7. Astsaturov IA, Meropol NJ, Alpaugh RK, Burtness BA, Cheng JD, McLaughlin S, Rogatko A, Xu Z, Watson JC, Weiner LM, Cohen SJ. Phase II and Coagulation Cascade Biomarker Study of Bevacizumab With or Without Docetaxel in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma. Am J Clin Oncol. 2010 May 7. [Epub ahead of print]
8. Andrews G, Lango M, Cohen R, Feigenberg S, Burtness B, Mehra R, Ahmed S, Nicolaou N, Gaughan J, Ridge JA. Non-surgical management of oropharyngeal, laryngeal and hypopharyngeal cancer: the Fox Chase Cancer Center experience. Head and Neck. Forthcoming 2010.
9. Argiris A, Ghebremichael M, Burtness B, Axelrod R, Deconti R, Forastiere AA. A phase II trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303). Cancer. Forthcoming 2010.
10. Turaka A, Li T, Sharma NK, Li L, Nicolaou N, Mehra R, Burtness B, Cohen RB, Lango MN, Horwitz EM, Ridge JA, Feigenberg SJ. Increased Recurrences Using Intensity-Modulated Radiation Therapy in the Postoperative Setting. Am J Clin Oncol. 2010 Nov 8. [Epub ahead of print].
11. Burtness B, M Gibson, B Egleston, R Mehra, L Thomas, R Sipples, M McGurk, J Lacy, S Watkins, JR Murren, AA Forastiere. Phase II Trial of Docetaxel/Irinotecan Combination in Advanced Esophageal Cancer. Ann Oncol. 2009;20:1242-8.
12. Burtness BA, Manola J, Axelrod R, et al. A randomized Phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: An Eastern Cooperative Oncology Group study. Annals Oncol. 2008;19:977-83.
13. Psyrri A, Egleston B, Weinberger P, Yu Z, Kowalski D, Sasaki C, Haffty B, Rimm D, Burtness B. Correlates and determinants of nuclear epidermal growth factor receptor content in an oropharyngeal cancer tissue microarray. Cancer Epidemiol Biomarkers Prev. 2008;17:1486-92.
14. Abu-Khalaf M, Juneja V, Chung G, DiGiovanna M, Wackers F, Lee F. and Burtness B. Long-term assessment of cardiac function after dose-dense and -intense sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) as adjuvant therapy for high risk breast cancer. Br Ca Treat Rep. 2007;104:341-9.
15. Yu A, PM Weinberger, C Sasaki, BL Egleston, WF Speier IV, B Haffty, D Kowalski, R Camp, D Rimm, E Vairaktaris, B Burtness, A Psyrri. Phosphorylation of Akt (Ser473) Predicts Poor Clinical Outcome in Oropharyngeal Squamous Cell Cancer Cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:553-558.
16. Zerkowski MP, RL Camp, BA Burtness, DL Rimm, and GG Chung. Automated image analysis of cyclooxygenase-2 (Cox-2) expression on a breast cancer tissue microarray. Cancer Invest. 2007;25:19-26.
17. Burtness B, Thomas L, Sipples R, McGurk M, Salikooti S, Christoforou M, Mirto G, Salem R, Sosa J, Kloss R, Rahman Z, Chung G, Lacy J, Murren JR. Phase II Trial of weekly docetaxel/irinotecan combination in advanced pancreatic cancer. Cancer J. 2007;13:257-262.
18. Heath EI, BA Burtness, L Kleinberg, R Salem, SC Yang, RF Heitmiller, MI Canto, JPS Knisely, M Topazian, E Montgomery, Y Pithavala, B Rohmiller, M Collier, AA Forastiere. Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with esophageal adenocarcinoma. Inv New Drug. 2006;24:135-40.
19. Chung GG, Yoon HH, Zerkowski MP, Rimm DL, Camp R, Harigopal M, LCharette LA, Burtness BA. Quantitative analysis of VEGF, Flt-1, and Flk-1 expression on a pancreatic cancer tissue microarray. Cancer. 2006;106:1677-84.
20. Kwong M S, GC Chung, L J Horvath, D Carter, A G Hsu, B A Ward, B Haffty, F Tavassoli, B A Burtness. Discordance between breast magnetic resonance imaging and residual disease on pathology in responders to neoadjuvant chemotherapy for stage III breast cancer. Cancer J. 2006;12:212-21.
21. Bossuyt V, O Fadare, M Martel, B Burtness, R Camp, F Tavassoli. Remarkably high frequency of EGFR expression in breast carcinomas with squamous differentiation. Int J Surg Pathol. 2005;13:319-327.
22. Burtness BA, Y Li, M Goldwasser, W Flood, B Mattar, A Forastiere. Phase III randomized trial of cisplatin + placebo versus cisplatin + C225, a monoclonal antibody directed to the epidermal growth factor receptor, for the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2005;23:8646-8654.
23. Psyrri A, Z Yu, PM Weinberger, C Sasaki, B Haffty, R Camp, D Rimm, B Burtness. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis. Clin Cancer Res. 2005;1:5856-62.
24. Psyrri A, M Kwong, L Lekakis, M Kassar, C Sasaki, L Wilson, B Haffty, Y H Son, D A Ross, P Weinberger, G Chung, D Zelterman, B A Burtness, D L Cooper. Cisplatin, 5-Fluorouracil and Leucovorin (PFL) Induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: long-term follow-up. J Clin Oncol. 2004;22(15):3061-9.
25. Gibson MK, S Abraham, TT Wu, B Burtness and A Forastiere. Epidermal growth factor receptor, p53 mutation and pathologic response predict survival in patients with locally advanced esophageal cancer treated with pre-operative chemoradiotherapy. Clin Cancer Res. 2003;9(17):6461-8.
26. Kleinberg L, JPS Knisely, R Heitmiller, M Zahurak, R Salem, B Burtness, E Heath, AA Forastiere. Mature survival results with preoperative cisplatin, protracted infusion 5-FU, and 44Gy radiotherapy for esophageal cancer. Int J Rad Onc Biol Phys. 2003;56:328-334.
27. Bleickardt E, R Rich, A Argiris, K Blum, A McKeon, H Tara, D Zelterman, G Tansino, B Burtness, MJ Davies, JR Murren. Phase I dose escalation trial of docetaxel plus irinotecan in patients with advanced cancer. Cancer Biol Ther. 2002;1:646-650.
28. Murren JR, G Pizzorno, SA DiStasio, A McKeon, K Peccerillo, A Gollerkeri, W MacMurran, BA Burtness, T Rutherford, X Li, PT Ho, A Sartorelli. Phase I study of perillyl alcohol in patients with refractory malignancies. Cancer Biol Ther. 2002;1:130-135.
29. Murren JR, K Peccerillo, SA DiStasio, X Li, JJ Leffert, G Pizzorno, BA Burtness, A McKeon, Y-c Cheng. Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer. Cancer Chemother Pharmacol. 2000;46:43-50.
30. Burtness B, M Belker, M Stoltz, KM Peccerillo, LA Lamb, SE Chmael, A McKeon, MB Clark, J Winship, JC Marsh, G Pizzorno, VT DeVita Jr. A phase I study of the antimetabolite (e)-2’-fluoromethylene-2’-deoxycytidine administered as a twice weekly infusion. Cancer J Sci Am. 2000;6:309-315.
31. Heath EI, BA Burtness, RF Heitmiller, R Salem, L Kleinberg, J Knisely, SC Yang, MA Talamini, HS Kaufman, MI Canto, T-T Wu, K Olukayode, AA Forastiere. Phase II evaluation of pre-operative chemoradiation and post- adjuvant chemotherapy for squamous cell and adenocarcinoma of the esophagus. J Clin Oncol. 2000;18:868.
32. Baselga J, D Pfister, MR Cooper, R Cohen, B Burtness, M Bos, G D'Andrea, A Seidman, L Norton, K Gunnett, J Falcey, V Anderson, H Waksal, J Mendelsohn. Phase I studies of anti-epidermal growth factor receptor chimeric monoclonal antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000;18:904.
33. Burtness BA, A Psyrri, M Rose, E D'Andrea, C Staugaard-Hahn, M Henderson-Bakas, S Mechanic, D Krause, E Snyder, R Corringham, A Deisseroth, DL Cooper. A phase I study of paclitaxel for mobilization of stem cells. Bone Marrow Transplant. 1999;23:311-315.
34. Pizzorno G, L Yee, BA Burtness, JC Marsh, JW Darnowski, MYW Chu, SH Chu, E Chu, JJ Leffert, RE Handschumacher, P Calabrisi. Phase I clinical and pharmacological studies of benzylacyclouridine (BAU), a uridine phosphorylase inhibitor. Clin Cancer Res. 1998;4:1165-1175.
35. Murren JR, S Anderson , J Fedele, G Pizzorno, D Belliveau, D Zelterman, BA Burtness, I Tocino, D Beidler, YC Cheng. Dose escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer. J Clin Onco 1997;15:148-157.

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Research Summary

My research involves working to develop new treatment techniques, using IMRT, that help men preserve erectile function following radiation therapy for prostate cancer. Currently, I am a co-primary investigator of this clinical trial at Fox Chase. I am also developing a technique to detect recurrent prostate cancer earlier using MR spectroscopy and repeat prostate biopsy, with funding from the Radiological Society of North America (RSNA). This will be available as part of a clinical trial. I am a co-author of several research papers and book chapters on prostate cancer, IMRT and testicular cancer.

I am dedicated to the future of radiation research. I serve on national committees of the Radiation Therapy Oncology Group (RTOG) and American Society for Therapeutic Radiology and Oncology (ASTRO). I twice received the Roentgen Resident/Fellow Research Award from the Radiological Society of North America (RSNA) during my residency at Fox Chase. In 2005, I received ASTRO's Young Investigator Award.

Selected Publications

1. Sharma NK, Li T, Chen DY, Pollack A, Horwitz EM, Buyyounouski MK. Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated with Androgen Deprivation Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys. 2010 Nov 2. [Epub ahead of print]. PubMed
2. Canter D, Greenberg RE, Horwitz EM, Kutikov A, Li J, Long C, Buyyounouski M, Boorjian SA. Implantation of electromagnetic transponders following radical prostatectomy for delivery of IMRT. Can J Urol. 2010 Oct;17(5):5365-9. PubMed
3. Buyyounouski MK. Androgen deprivation therapy in high-risk prostate cancer. Oncology (Williston Park). 2010 Aug;24(9):806, 809. PubMed
4. Buyyounouski MK, Balter P, Lewis B, D'Ambrosio DJ, Dilling TJ, Miller RC, Schefter T, Tomé W, Harris EE, Price RA Jr, Konski AA, Wallner PE. Stereotactic body radiotherapy for early-stage non-small-cell lung cancer: report of the ASTRO Emerging Technology Committee. Int J Radiat Oncol Biol Phys. 2010 Sep 1;78(1):3-10. Epub 2010 Jul 17. PubMed
5. Buyyounouski MK. Radiotherapy: PSA nadir predicts long-term mortality. Nat Rev Clin Oncol. 2010 Apr;7(4):188-90. PubMed
6. Buyyounouski MK, Price RA Jr, Harris EE, Miller R, Tomé W, Schefter T, Parsai EI, Konski AA, Wallner PE. Stereotactic body radiotherapy for primary management of early-stage, low- to intermediate-risk prostate cancer: report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee. Int J Radiat Oncol Biol Phys. 2010 Apr;76(5):1297-304. PubMed
7. Williams SG, Pickles T, Buyyounouski MK. Androgen deprivation therapy and prostate cancer duration. J Clin Oncol. 2009 Dec 1;27(34):e228; author reply e229. Epub 2009 Nov 2. PubMed
8. Sharma NK, Cohen RJ, Eade TN, Buyyounouski MK, Uzzo RG, Li J, Crawford K, Chen DY, McNeeley S, Horwitz EM. An intraoperative real-time sleeved seed technique for permanent prostate brachytherapy. Brachytherapy. 2010 Apr-Jun;9(2):126-30. Epub 2009 Oct 21. PubMed
9. Li JS, Jin L, Pollack A, Horwitz EM, Buyyounouski MK, Price RA Jr, Ma CM. Gains from real-time tracking of prostate motion during external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1613-20. Epub 2009 Oct 14. PubMed
10. Buyyounouski MK. Surveillance for stage I seminoma: better the devil you know than the devil you don't? Oncology (Williston Park). 2009 Aug;23(9):762, 764. PubMed
11. Kaplan DJ, Boorjian SA, Ruth K, Egleston BL, Chen DY, Viterbo R, Uzzo RG, Buyyounouski MK, Raysor S, Giri VN. Evaluation of the Prostate Cancer Prevention Trial Risk calculator in a high-risk screening population. BJU Int. 2010 Feb;105(3):334-7. Epub 2009 Aug 25. PubMed
12. Michalski JM, Lawton C, El Naqa I, Ritter M, O'Meara E, Seider MJ, Lee WR, Rosenthal SA, Pisansky T, Catton C, Valicenti RK, Zietman AL, Bosch WR, Sandler H, Buyyounouski MK, Ménard C. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. PubMed
13. Giri VN, Egleston B, Ruth K, Uzzo RG, Chen DY, Buyyounouski M, Raysor S, Hooker S, Torres JB, Ramike T, Mastalski K, Kim TY, Kittles R. Race, genetic West African ancestry, and prostate cancer prediction by prostate-specific antigen in prospectively screened high-risk men. Cancer Prev Res (Phila). 2009 Mar;2(3):244-50. Epub 2009 Feb 24. PubMed
14. Wang L, Hayes S, Paskalev K, Jin L, Buyyounouski MK, Ma CC, Feigenberg S. Dosimetric comparison of stereotactic body radiotherapy using 4D CT and multiphase CT images for treatment planning of lung cancer: evaluation of the impact on daily dose coverage. Radiother Oncol. 2009 Jun;91(3):314-24. PubMed
15. Lawton CA, Michalski J, El-Naqa I, Buyyounouski MK, Lee WR, Menard C, O'Meara E, Rosenthal SA, Ritter M, Seider M. RTOG GU Radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):383-7. PubMed
16. D'Ambrosio DJ, Li T, Horwitz EM, Chen DY, Pollack A, Buyyounouski MK. Does treatment duration affect outcome after radiotherapy for prostate cancer? Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1402-7. PubMed
17. Kaplan DJ, Crispen PL, Greenberg RE, Chen DY, Viterbo R, Buyyounouski MK, Horwitz EM, Uzzo RG. Residual prostate cancer after radiotherapy: a study of radical cystoprostatectomy specimens. Urology. 2008 Sep;72(3):654-8. PubMed
18. D'Ambrosio DJ, Ruth K, Horwitz EM, Chen DY, Pollack A, Buyyounouski MK. Does transurethral resection of prostate (TURP) affect outcome in patients who subsequently develop prostate cancer? Urology. 2008 May;71(5):938-41. PubMed
19. Eade TN, Horwitz EM, Ruth K, Buyyounouski MK, D'Ambrosio DJ, Feigenberg SJ, Chen DY, Pollack A. A comparison of acute and chronic toxicity for men with low-risk prostate cancer treated with intensity-modulated radiation therapy or (125)I permanent implant. Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):338-45. PubMed
20. D'Ambrosio DJ, Ruth K, Horwitz EM, Uzzo RG, Pollack A, Buyyounouski MK. How can men destined for biochemical failure after androgen deprivation and radiotherapy be identified earlier? Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1487-91. PubMed
21. Sharma NK, Li T, Chen DY, Pollack A, Horwitz EM, Buyyounouski MK. Intensity Modulated Radiation Therapy Reduces Gastrointestinal Toxicity in Patients Treated with Androgen Deprivation Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):S10. PubMed
22. Abramowitz MC, Li T, Buyyounouski MK, Ross E, Uzzo RG, Pollack A, Horwitz EM. The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer. 2008 Jan 1;112(1):55-60. PubMed
23. Williams SG, Buyyounouski MK, Pickles T, Kestin L, Martinez A, Hanlon AL, Duchesne GM. Percentage of biopsy cores positive for malignancy and biochemical failure following prostate cancer radiotherapy in 3,264 men: statistical significance without predictive performance. Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1169-75. PubMed
24. Buyyounouski MK, Hanlon AL, Horwitz EM, Pollack A. Interval to biochemical failure highly prognostic for distant metastasis and prostate cancer-specific mortality after radiotherapy. Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):59-66. PubMed
25. Giri VN, Beebe-Dimmer J, Buyyounouski M, Konski A, Feigenberg SJ, Uzzo RG, Hanks G, Godwin AK, Chen DY, Gordon R, Cescon T, Raysor S, Watkins-Bruner D. Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol. 2007 Nov;178(5):1920-4; discussion 1924. PubMed
26. Morgan PB, Hanlon AL, Horwitz EM, Buyyounouski MK, Uzzo RG, Pollack A. Timing of biochemical failure and distant metastatic disease for low-, intermediate-, and high-risk prostate cancer after radiotherapy. Cancer. 2007 Jul 1;110(1):68-80. PubMed
27. D'Ambrosio DJ, Cohen RB, Glass J, Konski A, Buyyounouski MK, Feigenberg SJ. Unexpected dementia following prophylactic cranial irradiation for small cell lung cancer: case report. J Neurooncol. 2007 Oct;85(1):77-9. PubMed
28. Eade TN, Al-Saleem T, Horwitz EM, Buyyounouski MK, Chen DY, Pollack A. Role of radiotherapy in ductal (endometrioid) carcinoma of the prostate. Cancer. 2007 May 15;109(10):2011-5. PubMed
29. Eade TN, Hanlon AL, Horwitz EM, Buyyounouski MK, Hanks GE, Pollack A. What dose of external-beam radiation is high enough for prostate cancer? Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):682-9. PubMed
30. D'Ambrosio DJ, Hanlon AL, Al-Saleem T, Feigenberg SJ, Horwitz EM, Uzzo RG, Pollack A, Buyyounouski MK. The proportion of prostate biopsy tissue with Gleason pattern 4 or 5 predicts for biochemical and clinical outcome after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1082-7. PubMed
31. Morgan PB, Hanlon AL, Horwitz EM, Buyyounouski MK, Uzzo RG, Pollack A. Radiation dose and late failures in prostate cancer. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1074-81. PubMed
32. Alcantara P, Hanlon A, Buyyounouski MK, Horwitz EM, Pollack A. Prostate-specific antigen nadir within 12 months of prostate cancer radiotherapy predicts metastasis and death. Cancer. 2007 Jan 1;109(1):41-7. PubMed
33. Price RA Jr, Hannoun-Levi JM, Horwitz E, Buyyounouski M, Ruth KJ, Ma CM, Pollack A. Impact of pelvic nodal irradiation with intensity-modulated radiotherapy on treatment of prostate cancer. Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):583-92. PubMed
34. Pollack A, Hanlon AL, Horwitz EM, Feigenberg SJ, Konski AA, Movsas B, Greenberg RE, Uzzo RG, Ma CM, McNeeley SW, Buyyounouski MK, Price RA Jr. Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):518-26. PubMed
35. Buyyounouski MK, Hanlon AL, Eisenberg DF, Horwitz EM, Feigenberg SJ, Uzzo RG, Pollack A. Defining biochemical failure after radiotherapy with and without androgen deprivation for prostate cancer. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1455-62. PubMed
36. Buyyounouski MK, Hanlon AL, Horwitz EM, Uzzo RG, Pollack A. Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1291-8. PubMed
37. Buyyounouski MK, Klump WJ, Konski A, Wu H, Adler LP. FDG PET imaging of signet-ring cell adenocarcinoma of the stomach. Clin Nucl Med. 2005 Feb;30(2):118-9. PubMed
38. Buyyounouski MK, Hanlon AL, Price RA Jr, Horwitz EM, Feigenberg SJ, Pollack A. In regard to Selek et al. erectile dysfunction and radiation dose to penile base structures: a lack of correlation. IJROBP 2004;59:1039-1046. Int J Radiat Oncol Biol Phys. 2004 Dec 1;60(5):1664-5. PubMed
39. Buyyounouski MK, Horwitz EM, Uzzo RG, Price RA, McNeeley SW, Azizi D, Hanlon AL, Milestone BN, Pollack A. The radiation doses to erectile tissues defined with magnetic resonance imaging after intensity-modulated radiation therapy or iodine-125 brachytherapy. Int J Radiat Oncol Biol Phys. 2004 Aug 1;59(5):1383-91. PubMed
40. Buyyounouski MK, Horwitz EM, Price RA, Hanlon AL, Uzzo RG, Pollack A. Intensity-modulated radiotherapy with MRI simulation to reduce doses received by erectile tissue during prostate cancer treatment. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):743-9. PubMed
41. Buyyounouski MK, Horwitz EM, Hanlon AL, Uzzo RG, Pollack A. Re: improved clinical staging system combining biopsy laterality and TNM stage for men with T1c and T2 prostate cancer: results from the search database. J Urol. 2004 Mar;171(3):1246-7. PubMed
42. Buyyounouski MK, Horwitz EM, Hanlon AL, Uzzo RG, Hanks GE, Pollack A. Positive prostate biopsy laterality and implications for staging. Urology. 2003 Aug;62(2):298-303. PubMed
43. Kaminski JM, Nguyen K, Buyyounouski M, Pollack A. Prostate cancer gene therapy and the role of radiation. Cancer Treat Rev. 2002 Feb;28(1):49-64. PubMed
44. Rubin MA, Buyyounouski M, Bagiella E, Sharir S, Neugut A, Benson M, de la Taille A, Katz AE, Olsson CA, Ennis RD. Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology. 1999 Mar;53(3):542-7. Review. PubMed

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Research Summary

My major research interests include image guidance, dosimetry planning/treatment assessment for intensity-modulated radiation therapy (IMRT), MR guided high intensity focused ultrasound (HIFU) surgery/drug enhancement for gene therapy and chemotherapy in combination with radiation therapy.

Selected Publications

1. Chen L, Mu Z, Hachem P, Ma C-M, Wallentine A and Pollack A. MR-guided focused ultrasound: enhancement of intratumoral uptake of [3H]-docetaxel in vivo. Phys. Med. Biol. 55 (2010) 7399–7410)
2. Chen L, Paskalev K, Xu X, Zhu J, Wang L, Price RA, Hu W, Feigenberg SJ, Horwitz EM, Pollack A, Ma CM. Prostate Cancer IMRT: Rectal Dose Variation During the Course of the Treatment in Image Guided Radiation Therapy. Radiother Oncol. 2010 May;95(2):198-202. PubMed
3. Chen L, Nguyen T-B, Jones E, Chen Z, Luo W, Wang L, Price RA, Pollack A and Ma C-M. MRI-Based Treatment Planning for Prostate IMRT: Creation of Digitally Reconstructed Radiographs (DRR). International Journal of Radiation Oncology Biology Physics. 2007;68:(3):903-11.
4. Chen L, Price RA Jr., Wang L, Li JS, Qin L, Ding M, Palacio E, T-B Nguyen, Ma C-M, Pollack A. Dosimetric evaluation of MRI-based treatment planning for prostate cancer. Phys Med Biol. 2004;49:5157-70.
5. Chen L, Price RA Jr., Wang L, Li JS, Qin L, Shawn M, Ma C-M, Freedman GM and Pollack A. MRI-Based Treatment Planning for Radiotherapy: Dosimetric Verification for Prostate IMRT. Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):636-47. PubMed

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Human Epithelial Ovarian Cancer: Development, Progression and Metastasis

The overall goal of our research is to discover ways to improve the treatment of epithelial ovarian cancer (EOC). Most cases of EOC are diagnosed at advanced stage when disease has spread beyond the ovary. From a clinical standpoint, EOC metastases and ascites production are perhaps the most significant cause of morbidity and mortality in patients because they can affect multiple vital organs in the abdominal cavity. At present, the cellular mechanisms regulating EOC metastasis remain poorly understood. Our laboratory is interested in defining the precise molecular mechanisms of peritoneal dissemination of ovarian cancer cells to identify specific molecular targets for therapeutic intervention in patients. Using a combination of in vitro and in vivo approaches, we hope to better understand EOC tumor biology at the cellular level as well as disease development and progression in animals. Several projects in our laboratory are focused on the cellular pathways involved in ovarian cancer cell migration, attachment and invasion. Specifically, we are interested in the understanding the role of focal adhesion signaling in EOC migration and invasion with the ultimate goal of identifying therapeutic agents that inhibit the spread of ovarian cancer.

To facilitate our studies, we have developed immunocompetent mouse models of EOC. We developed the first transgenic model of spontaneous EOC by expressing the SV40 TAg under transcriptional control of the Müllerian inhibiting substance type II receptor (MISIIR) gene promoter. One transgenic line of MISIIR-Tag mice develop spontaneous EOC with pathological features of serous EOC. Like human EOC, female with significant tumor burden exhibit no symptoms of illness, disease dissemination is typically restricted to the peritoneum and tumor cells share many molecular features with human tumors. We have also isolated a transgenic line of mice that express the transgene at low levels, but do not develop ovarian tumors. These mice can serve as syngeneic recipients for orthotopic implantation of murine ovarian carcinoma (MOVCAR) cells isolated from MISIIR-Tag mice. These transgenic mice, as well as tissues and cell lines developed from them are currently being utilized in conjunction with established human ovarian carcinoma cell lines to study the mechanisms of EOC tumor progression and metastasis.

Selected Publications

1. Liang S, Yang N, Pan Y, Deng S, Lin X, Katsaros KF, Hamilton TC, Connolly DC, Coukos G, Zhang L. Expression of activated PIK3CA in ovarian surface epithelium results in hyperplasia but not tumor formation. PLoS ONE 4(1):e4295. Epub 2009 Jan 27. PubMed
2. Choi YS, Hoory T, Monie A, Wu A, Connolly D, Hung, C-F. α-Galactosylceramide enhances the protective and therapeutic effects of tumor cell based vaccines for ovarian tumors. Vaccine. 2008;26(46):5855-5863. PubMed
3. Melikechi N, Ding H, Rock S, Marcano OA, Connolly D. Laser-induced breakdown spectroscopy of whole blood and other liquid organic compounds. In: Optical Diagnostic and Sensing VIII (Cote G, Priezzhev AV, eds.). Proceeding of SPIE 6863, 68630O1-7, 2008;DOI: 10.1117/12.761901.
4. Melikechi N, Ding H, Marcano OA, Rock S, Connolly D. Laser-induced breakdown spectroscopy of alcohols and proteins solutions. AIP Proceedings: Atomic, Molecular, and Optical Physics. 2008;992:1177-1182.
5. Hensley H, Quinn BA, Wolf RL, Litwin S, Mabuchi S, Williams SJ, Williams C, Hamilton TC, Connolly DC. Magnetic resonance imaging for detection and determination of tumor volume in a genetically engineered mouse model of ovarian cancer. Cancer Biol Ther. 2007;6:1717-1725. PubMed
6. Mabuchi S, Altomare DA, Connolly DC, Klein Szanto A, Litwin S, Hoelzle MK, Hensley HH, Hamilton TC, Testa JR. RAD001 delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res. 2007;67:2408-2413. PubMed
7. Pieretti-Vanmarcke R, Donahoe PK, Pearsall L, Connolly DC, Dinulescu DM, Halpern EF, Seiden MV, McLaughlin DT. MIS enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Proc Natl Acad Sci USA. 2006;103:17426-17431. PubMed
8. Connolly DC, Bao R, Nikitin AY, Stephens KC, Poole T, Hua X, Harris SS, Vanderhyden BC, Hamilton TC. Female mice chimeric for the expression of the SV40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 2003;63:1389-1397. PubMed

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Overview of Research Interests

Health Effects of Low Dose Radiation

Whereas the carcinogenic nature of high dose radiation is well established, the health effects of low dose radiation are still being debated.  The current radiation safety paradigm is based on the linear no-threshold (LNT) premise that even the smallest amount of radiation may cause DNA damage and mutations increasing the risk of cancer.  Though mutations are essential in the carcinogenic process, mutations do not necessarily result in clinical cancer.   Autopsy studies have shown that the presence of cancer cells is not a decisive factor in the occurrence of clinical cancer.  On the other hand, suppression of immune system more than doubles the cancer risk in organ transplant patients, indicating its key role in keeping occult cancers in check.  LNT model pays exclusive attention to DNA damage, which is not a decisive factor, and completely ignores immune system response, which is an important factor, and so is not scientifically justifiable.

The biological effects of low dose radiation are similar to that of moderate exercise in that they both lead to slightly increased production of free radicals stimulating the body’s defensive mechanisms such as increased antioxidant capacity and the immune system.  Thus, low dose radiation may be expected to reduce rather than increase cancers, since the immune system plays an extremely important role in preventing cancers.  This has been observed in many controlled animal studies.  The increased antioxidants may also help to reduce aging-related diseases since oxidative damage has been implicated in many of these diseases.  External administration of antioxidants has failed to reduce diseases in clinical trials, possibly because there may not have been sufficient bioavailability of the antioxidants in the relevant organs to reduce the oxidative damage.  Administration of large doses of antioxidants can interfere with important cellular signaling mechanisms, resulting in worsening of health and so is not recommended.  Thus we are at an impasse in dealing with the underlying cause of aging-related diseases.  Low dose radiation may provide a solution to this impasse by endogenous production of antioxidants in the relevant organs.  Controlled animal studies have shown reduction of many of these diseases using low dose radiation, and some human studies have also shown promising results.  Low dose radiation can be used to supplement traditional treatments which address the symptoms of the diseases, in order to reduce the recurrence of the diseases.  The increased antioxidants from low dose radiation may also reduce the adverse side effects of cancer therapies, since many of these are caused by oxidative damage also.  Another potential application of low dose radiation may be in providing the benefits of exercise to the infirm that are unable to exercise.  However, study of these potential beneficial effects is not presently feasible because of the LNT model based radiation safety regulations and the resulting fear of low dose radiation among the public.  A paradigm shift in radiation safety is warranted to enable the study of potential beneficial effects of low dose radiation.

Current research projects

Application of Low Dose Radiation Adaptive Response to Control Parkinson’s disease in a rat model:

Our hypothesis is that low dose radiation elevates the level of antioxidants in substantia nigra in rat brain and reduces Parkinson’s disease symptoms in the 6-OHDA-lesion model of the disease.  This study is in collaboration with a team at Temple University Hospital Neurology Department led by Barbara Krynska, Ph.D.  Experiments are in progress for this study.

Selected Publications

1. Doss M, Shifting the Paradigm in Radiation Safety, Dose Response, 2012, Advance online publication.
2. Doss M, Kolb HC, Zhang JJ, Bélanger MJ, Stubbs JB, Stabin MG, Hostetler ED, Alpaugh RK, von Mehren M, Walsh JC, Haka M, Mocharla VP, Yu JQ. Biodistribution and Radiation Dosimetry of the Integrin Marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med. 2012, Accepted for Publication.
3. Zhu Z, Doss M, Tan H, Feigenberg S, Yu JQ. Inadvertent intraarterial injection of ¹⁸F-FDG: a case report and literature review of hot forearm and hot hand signs. J Nucl Med Technol. 2011 Dec;39(4):249-51. Epub 2011 Aug 24. PubMed
4. Reddy S, Shaller CC, Doss M, Shchaveleva I, Marks JD, Yu JQ, Robinson MK. Evaluation of the anti-HER2 C6.5 diabody as a PET radiotracer to monitor HER2 status and predict response to trastuzumab treatment. Clin Cancer Res. 2011 Mar 15;17(6):1509-20. Epub 2010 Dec 21.PubMed
5. Doss M, Zhang JJ, Bélanger MJ, Stubbs JB, Hostetler ED, Alpaugh K, Kolb HC, Yu JQ. Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl Med Commun. 2010 Dec;31(12):1016-24. PubMed
6. Yu JQ, Milestone BN, Parsons RB, Doss M, Haas N. Findings of intramediastinal gossypiboma with F-18 FDG PET in a melanoma patient. Clin Nucl Med. 2008 May;33(5):344-5. PubMed
7. Robinson MK, Doss M, Shaller C, Narayanan D, Marks JD, Adler LP, Gonzalez Trotter DE, Adams GP. Quantitative immuno-positron emission tomography imaging of HER2-positive tumor xenografts with an iodine-124 labeled anti-HER2 diabody. Cancer Res. 2005 Feb 15;65(4):1471-8. PubMed
8. Konski A, Doss M, Milestone B, Haluszka O, Hanlon A, Freedman G, Adler L. The integration of 18-fluoro-deoxy-glucose positron emission tomography and endoscopic ultrasound in the treatment-planning process for esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1123-8. PubMed
9. González Trotter DE, Manjeshwar RM, Doss M, Shaller C, Robinson MK, Tandon R, Adams GP, Adler LP. Quantitation of small-animal (124)I activity distributions using a clinical PET/CT scanner. J Nucl Med. 2004 Jul;45(7):1237-44. PubMed

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Protein Structure Prediction in Biology and Medicine

The Dunbrack group concentrates on research in computational structural biology, including homology modeling, fold recognition, molecular dynamics simulations, statistical analysis of the PDB, and bioinformatics. In developing these methods, we use methods from various areas of mathematics and computer science, including Bayesian statistics and computational geometry. We place an emphasis on large-scale benchmarking of new methods and comparison with existing methods. We are interested in applying comparative modeling to important problems in various areas of biology. Areas of particular interest include DNA repair, proteases and other peptide-binding protein families, and membrane proteins.

Our software development uses visual programming environments, such as Visual Studio, and modern programming languages such as object-oriented C++ and C#. Our goal is to produce easy-to-use, professional software for use in our own research as well as to be distributed to other research groups around the world.

Check out DashPDB, a Mac OS X Dashboard widget, designed to give quick access to the RCSB Protein Data Bank!
Download Now  | Installation Instructions (PDF, requires Adobe Acrobat^®)

Selected Publications

1. Li C, Andrake M, Dunbrack R, Enders GH. A bi-functional regulatory element in human somatic Wee1 mediates cyclin A/Cdk2 binding and Crm1-dependent nuclear export. Molec Cell Biol. Forthcoming 2009. PubMed
2. Berkholz DS, Shapovalov MV, Dunbrack RL Jr, Karplus PA. Conformation dependence of backbone geometry in proteins. Structure. 2009;17:1316-25. PubMed
3. Krivov GG, Shapovalov MV, Dunbrack RL Jr. Improved prediction of protein side-chain conformations with SCWRL4. Proteins. 2009;77:778-95. PubMed
4. Wang Q, Canutescu AA, Dunbrack RL Jr. SCWRL and MollDE: computer programs for side-chain conformation prediction and homology modeling. Nat Protoc. 2008;3:1832-47. PubMed
5. Xu Q, Canutescu AA, Wang G, Shapovalov M, Obradovic Z, Dunbrack RL Jr. Statistical ananlysis of interface similarity in crystals of homologous proteins. J Mol Biol. 2008;381:487-507. PubMed
6. Shapovalov MV, Dunbrack RL Jr. Statistical and conformational analysis of the electron density of protein side chains. Proteins. 2007;66:279-303. PubMed
7. Xu Q, Canutescu A, Obradvic Z, Dunbrack RL Jr. ProtBuD: a database of biological unit structures of protein families and superfamilies. Bioinformatics 2006;22:2876-82. PubMed
8. Wang G, Dunbrack RL Jr. PISCES: recent improvements to a PDB sequence culling server. Nucleic Acids Res. 33:W94-W98, 2005. PubMed

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Research Overview

Brian Egleston, PhD received his doctorate in biostatistics from the Johns Hopkins University. He also has a Master of Public Policy from the University of Chicago.  His interests include the development of methodology for causal inference, accounting for missing data, and investigating the effects of survey response fatigue. Many of his collaborative analyses have involved the application of state of the art approaches including hierarchical Bayesian, propensity score, competing risk, cost effectiveness, and latent variable methods.

Selected Publications

1. Egleston BL, Miller SM, Meropol NJ. The impact of misclassification due to survey response fatigue on estimation and identifiability of treatment effects. Statistics in Medicine 2011. 30(30):3560-72.
2. Egleston BL, Cropsey KL, Lazev AB, Heckman CJ. Tutorial on principal stratification-based sensitivity analysis: Application to smoking cessation studies. Clinical Trials. 2010;7(3):286-98. PubMed
3. Egleston BL, Chandler DW, Dorgan JF. Validity of estimating non-SHBG bound testosterone and estradiol from total hormone measurements in boys and girls. Annals of Clinical Biochemistry. 2010;47(Pt 3):233-41. PubMed
4. Egleston BL, Dunbrack RL Jr, Hall MJ. Clinical trials that explicitly exclude gay and lesbian patients. New England Journal of Medicine. 2010;362(11):1054-5. PubMed
5. Egleston BL, Scharfstein DO, MacKenzie E. On estimation of the survivor average causal effect in observational studies when important confounders are missing due to death. Biometrics. 2009;65(2):497-504. PubMed
6. Egleston BL, Wong YN. Sensitivity analysis to investigate the impact of a missing covariate on survival analyses using cancer registry data. Stat Med. 2009;28(10):1498-511. PubMed

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Research Interests

Breast cancer remains one of the most common malignancies among women, second only in incidence to lung cancer. For the first time since 1950, breast cancer death rates for American women declined nearly 5% between 1989 and 1992. Two plausible explanations for the decline are an increase in breast cancer awareness leading to early detection, and adjuvant systemic therapy for both node positive and node negative breast cancer. In an effort to contribute to the reduction of both the incidences of breast cancer and the morbidity and mortality due to this disease, we have developed a multidisciplinary program encompassing basic, clinical, and prevention and control research.

Selected Publications

1. Finn RS, Bengala C, Ibrahim N, Strauss LC, Fairchild J, Sy O, Roche H, Sparano J, Goldstein LJ. Phase II trial of dasatinib in triple-negative breast cancer: results of study CA 180059. Cancer Res. 2009;69(2):237S-237S.
2. Goldstein LJ, Sparano JA. Twenty-One-Gene Assay: Challenges and Promises in Translating Personal Genomics and Whole-Genome Scans Into Personalized Treatment of Breast Cancer REPLY. J Clin Oncol. 2009 Mar;27(8):1338-9.
3. Turaka A, Freedman GM, Li T, Anderson PR, Swaby R, Nicolaou N, Goldstein L, Sigurdson ER, Bleicher RJ. Young age is not associated with increased local recurrence for DCIS treated by breast-conserving surgery and radiation. J Surg Oncol. 2009 Jul 1;100(1):25-31.
4. Freedman GM, Anderson P, Litwin S, Swaby R, Nicolaou N, Sigurdson E, Ma C, Watkins-Bruner D, Morrow M, Goldstein L. Five-year Results of a Phase II Study of Hypofractionated IMRT with an Incorporated Boost for Breast Cancer. International Journal of Radiation Oncology Biology Physics. 2009;75(3):S77-S77.
5. Swaby RF, Wang M, Sparano JA, Bhalla K, Meropol NJ, Falkson CI, Pellegrino CM, Klein P, Goldstein LJ, Sledge GW. A Phase II Study of the Histone Deacetylase Inhibitor, Vorinostat, in Combination with Trastuzumab in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER-2 Amplified Breast Cancer Resistant to Transtuzumab-Containing Therapy: (E1104) a Trial of the Eastern Cooperative Oncology Group. Cancer Res. 2009 Dec;69(24):793S-793S.
6. Goldstein LJ. Experience in Phase I Trials and an Upcoming Phase II Study with uPA Inhibitors in Metastatic Breast Cancer. 2008;:25-8.
7. Badve SS, Baehner FL, Gray RP, Childs BH, Maddala T, Liu ML, Rowley SC, Shak S, Perez EA, Shulman LJ, Martino S, Davidson NE, Sledge GW, Goldstein LJ, Sparano JA. Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol. 2008 May 20;26(15):2473-81.
8. Carlson RW, Moench S, Hurria A, Balducci L, Burstein HJ, Goldstein LJ, Gradishar WJ, Hughes KS, Jahanzeb M, Lichtman SM, Marks LB, McClure JS, McCormick B, Nabell LM, Pierce LJ, Smith ML, Topham NS, Traina TA, Ward JH, Winer EP. NCCN Task Force Report: breast cancer in the older woman. J Natl Compr Canc Netw. 2008;6 Suppl 4:S1-S25; quiz S26-S27.
9. Chu QS, Cianfrocca ME, Goldstein LJ, Gale M, Murray N, Loftiss J, Arya N, Koch KM, Pandite L, Fleming RA, Paul E, Rowinsky EK. A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer. Clin Cancer Res. 2008 Jul;14(14):4484-90.
10. Turaka A, Freedman G, Li T, Bleicher R, Swaby R, Nicolaou N, Goldstein L, Sigurdson E, Anderson P. Young age is not associated with increased local recurrence for DCIS treated by breast-conserving surgery and radiation. International Journal of Radiation Oncology Biology Physics. 2008;72(1):S151-S152.
11. Goldstein LJ, Gray R, Badve S, Childs BH, Yoshizawa C, Rowley S, Shak S, Baehner FL, Ravdin PM, Davidson NE, Sledge GW, Perez EA, Shulman LN, Martino S, Sparano JA. Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol. 2008 Sep 1;26(25):4063-71.
12. Goldstein LJ, O'Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol. 2008 Sep 1;26(25):4092-9.
13. Borghaei H, Katherine Alpaugh R, Bernardo P, Palazzo IE, Dutcher JP, Venkatraj U, Wood WC, Goldstein L, Weiner LM. Induction of Adaptive Anti-HER2/neu Immune Responses in a Phase 1B/2 Trial of 2B1 Bispecific Murine Monoclonal Antibody in Metastatic Breast Cancer (E3194): A Trial Coordinated by the Eastern Cooperative Oncology Group. J Immunother. 2007 May/June;30(4):455-67.
14. O'Grady MA, Gitelson E, Swaby RF, Goldstein LJ, Sein E, Keeley P, Miller B, Li T, Weinstein A, Cohen SJ. Development and implementation of a medical oncology quality improvement tool for a regional community oncology network: the fox chase cancer center partners initiative. J Natl Compr Canc Netw. 2007 Oct;5(9):875-82.
15. Hayes DF, Thor AD, Dressler LG, Weaver D, Edgerton S, Cowan D, Broadwater G, Goldstein LJ, Martino S, Ingle JN, Henderson IC, Norton L, Winer EP, Hudis CA, Ellis MJ, Berry DA. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007 Oct;357(15):1496-506.
16. Abramowitz MC, Li T, Nicolaou N, Anderson P, Goldstein L, Morrow M, Freedman G. Smoking does not affect the clinical presentation of breast cancer. International Journal of Radiation Oncology Biology Physics. 2007;69(3):S228-S228.
17. Freedman GM, Anderson PR, Goldstein LJ, Ma CM, Li J, Swaby RF, Litwin S, Watkins-Bruner D, Sigurdson ER, Morrow M. Four-week course of radiation for breast cancer using hypofractionated intensity modulated radiation therapy with an incorporated boost. Int J Radiat Oncol Biol Phys. 2007 Mar 20;68(2):347-53.
18. Carlson RW, O'Neill AM, Goldstein LJ, Sikic BI, Abramson N, Stewart JA, Davidson NE, Wood WC. A pilot phase II trial of valspodar modulation of multidrug resistance to paclitaxel in the treatment of metastatic carcinoma of the breast (E1195): A trial of the eastern cooperative oncology group. Cancer Invest. 2006 Nov;24(7):677-81.
19. Morrow M, Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted?. J Clin Oncol. 2006 Jun 20;24(18):2694-6.
20. Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION. 2006 Apr;295(14):1658-67.
21. Hayes DF, Thor A, Dressler L, Weaver D, Broadwater G, Goldstein L, Martino S, Ingle J, Henderson IC, Berry D. HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344. J Clin Oncol. 2006 Jun;24(18):5S-5S.
22. Manne SL, Ostroff JS, Norton TR, Fox K, Goldstein L, Grana G. Cancer-related relationship communication in couples coping with early stage breast cancer. Psychooncology. 2006 Mar;15(3):234-47.
23. Manne SL, Ostroff JS, Norton TR, Fox K, Grana G, Goldstein L. Cancer-specific self-efficacy and psychosocial and functional adaptation to early stage breast cancer. Ann Behav Med. 2006 Apr;31(2):145-54.
24. Freedman GM, Anderson P, Goldstein L, Litwin S, Li J, Watkins-Bruner D, Nicolaou N, Swaby R, Sigurdson E, Morrow M. A phase II study of four-week radiation for breast cancer using hypofractionated intensity modulated radiation therapy (IMRT) with an incorporated boost. International Journal of Radiation Oncology Biology Physics. 2006;66(3):S176-S176.
25. Freedman GM, Anderson P, Li TY, Ross E, Swaby R, Goldstein L. Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant radiation and tamoxifen. Cancer. 2006 Dec;107(11):2552-8.
26. Goldstein LJ. Controversies in adjuvant endocrine treatment of premenopausal women. Clinical Breast Cancer. 2006 Feb;6 Suppl 2:S36-40.
27. Chu Q, Goldstein L, Murray N, Rowinsky E, Cianfrocca M, Gale M, Ho P, Paul E, Loftiss J, Pandite L. A phase I, open-label study of the safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients. J Clin Oncol. 2005 Part 1 Suppl. S JUN 1;23(16):192S-192S.
28. Chu Q, Rowinsky E, Goldstein L, Cianfrocca M, Murray N, Gale M, Ho PT, Loftiss JI, Paul E, Pandite L. Phase I study of lapatinib (GW572016) in combination with letrozole in cancer patients. EJC Supplements. 2005 Oct;3(2):119.
29. Freedman GM, Anderson P, Li T, Ross E, Swaby R, Goldstein L. Selection of breast cancer patients for an aromatase inhibitor after radiation and tamoxifen. International Journal of Radiation Oncology Biology Physics. 2005 2019 Suppl. 1;63(2):S242-S242.
30. Goldstein LJ, Cohen RB, Swaby R, Gallo JM, Bartz R, Muehlenweg B, Bevan P, Wilhelm OG. Antiproteolytic therapy targeting urokinase-plasminogen activator for the treatment of breast cancer - a phase I study. Clin Cancer Res. 2005 Part;11(24):9060S-9061S.
31. Gurtle JS, Goldstein L, Delprete S, Tjulandin S, Semiglazov V, Sternas L, Michiels B, Gilles E. Trabectedin in third line breast cancer: A multicenter, randomized, phase II study comparing two administration regimens. J Clin Oncol. 2005 Part 1 Suppl. S JUN 1;23(16):34S-34S.
32. Goldstein LJ, O'Neill A, Sparano J, Perez E, Shulman L, Martino S, Davidson N. E2197: Phase III AT (doxorubicin/docetaxel) vs. AC (doxorubicin/cyclophosphamide) in the adjuvant treatment of node positive and high risk node negative breast cancer. J Clin Oncol. 2005 Part 1 Suppl. S JUN 1;23(16):7S-7S.

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Identifying and Targeting Signaling Hubs in Cancer

Our laboratory is interested in defining the changes in cell signaling that occur as tumors initiate, progress, and develop resistance to drugs, with the ultimate goal of inhibiting these processes. Part of our research focuses on study of NEDD9, a member of the Cas protein family. NEDD9 acts as a scaffold for signaling proteins that play essential roles in cancer progression and normal organismal development.  Part of the laboratory also addresses the biological functions of NEDD9-interacting proteins, including particularly an oncogenic kinase, Aurora-A.  Complementary projects use computer-based bioinformatic approaches to look for genes that sensitize cells to therapies targeted against cancer-promoting proteins such as EGFR. We hope through these studies to better define the interactions of signaling pathways in malignant versus normal cells, allowing improvements in cancer diagnosis and treatment.

Selected Publications

1. Plotnikova OV, Nikonova AS, Loskutov YV, Kozyulina PY, Pugacheva EN, Golemis EA. Calmodulin activation of Aurora-A (AURKA) is required during ciliary disassembly and in mitosis. Mol Biol Cell 2012 Jul;23(14):2658-70. Pubmed
2. Seeger-Nukpezah T, Golemis EA. The extracellular matrix and ciliary signaling. Current Opin Cell Biol 24, Epub July 19 2012. Pubmed
3. Mehra R, Serebriiskii IG, Dunbrack RL, Robinson MK, Burtness B, Golemis EA. Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer. Drug Resistance Updates. 2011 Dec;14(6):260-79. Pubmed
4. Ratushny V, Pathak HB, Beeharry N, Tikhmyanova N, Xiao F, Li T, Litwin S, Connolly DC, Yen TJ, Weiner LM, Godwin AK, Golemis EA. Dual inhibition of SRC and Aurora kinases induces postmitotic attachment defects and cell death. Oncogene. 2012 Mar 08;31(10):1217-27. Pubmed
5. Plotnikova, O.V., Pugacheva, E.P., and Golemis, E.A., Aurora-A kinase activity influences calcium signaling in kidney cells. J. Cell Biol 193:1021-1032, 2011. Pubmed
6. Astsaturov I, Ratushny V, Sukhanova A, Einarson M, Bagnyukova T, Zhou Y, Devarajan K, Silverman JS, Tikhmyanova N, Skobeleva N, Pecherskaya A, Nasto R, Jablonski SJ, Serebriiskii IG, Weiner LM, and Golemis EA. Synthetic lethal screen of an EGFR-centered signaling network defines clusters of proteins contributing to drug resistance. Science Signaling, 3(140):ra67, 2010. Pubmed
7. Plotnikova OV, Pugacheva EN, Dunbrack RL, Jr., and Golemis EA. Rapid calcium-dependent activation of Aurora-A kinase. Nature Commun. 1 : 64 doi: 10.1038/ncomms1061 Epub September 7, 2010. Pubmed
8. Singh, M.K., Izumchenko, E., Klein-Szanto, A., Egleston, B.L., Wolfson, M., Golemis, E.A. Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking Nedd9. Cancer Research 70:8907-8916, 2010. Pubmed
9. Izumchenko E, Singh MK, Plotnikova OV, Tikhmyanova N, Little JL, Serebriiskii IG, Seo S, Kurokawa M, Egleston BL, Klein-Szanto A, Pugacheva EN, Hardy RR, Wolfson M, Connolly DC, Golemis EA. HEF1/CAS-L/NEDD9 null status limits mouse mammary tumor progression. Cancer Res. 2009 Sep 15;69(18):7198-206. Pubmed
10. Singh MK, Dadke D, Nicolas E, Serebriiskii IG, Apostolou S, Canutescu A, Egleston BL, and Golemis EA. A novel Cas-family member, HEPL, regulates FAK and cell spreading. Mol Biol Cell, 19:1627-1636, 2008. Pubmed
11. Pugacheva EN, Jablonski SA., Hartman TR, Henske EP, and Golemis EA. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 2007 Jun 29;129(7):1351-63. Pubmed

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Drug Resistance Mechanisms

Cellular resistance to chemotherapeutic agents is a major obstacle to cancer treatment. ATP-binding cassette (ABC) transporters are involved in resistance by virtue of their ability to extrude drugs from the cell. Multidrug Resistance Proteins (MRPs) are drug efflux pumps that reside in the C family of ABC transporters - one of the largest families of ABC transporters. Similar to other family members, MRP7 is able to transport amphipathic anions, and MRP7 confers resistance to a wide variety of anticancer agents including taxanes, vinca alkaloids and nucleoside- based agents. Our laboratory is using a variety of models, biochemical, cellular and In vivo to further examine the role of MRP7 in cellular resistance.

Selected Publications

1. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, Hopper-Borge E, Bonora S, Di Perri G, Back DJ, Khoo S, Pirmohamed M, Owen A. Genetic variants of ABCC10, a novel tenofovir. J Infect Dis. 2011 Jul;204(1):145-53. PubMed
2. Hopper-Borge EA, Churchill T, Paulose C, Nicolas E, Jacobs JD, Ngo O, Kuang Y, Grinberg A, Westphal H, Chen ZS, Klein-Szanto AJ, Belinsky MG, Kruh GD. Contribution of Abcc10 (Mrp7) to In Vivo Paclitaxel Resistance as Assessed in Abcc10-/- Mice. Cancer Res. 2011 May 15;71(10):3649-3657. PubMed
3. Hopper-Borge E, Nasto RN, Ratushny V, Weiner LM, Golemis EA, Astsaturov I. Mechanisms of tumor resistance to EGFR-targeted therapies. Exp Opin Ther Targets. 2009;13(3):339-362. PubMed
4. Zhou Y, Hopper-Borge E, Shi Z, Shen T, Furukawa T, Akiyama S, Peng XX, Huang XC, Ashby C, Kruh GD, Chen ZS. Cepharanthine is a potent reversal agent for MRP7-mediated multidrug resistance. Biochem Pharmacol. 2009;77:993-1001. PubMed
5. Hopper-Borge E, Xu X, Shen T, Shi Z, Chen ZS, Kruh GD. Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res. 2009;69:178-184. PubMed
6. Risinger AL, Jackson EM, Polin LA, Helms GL, LeBoeuf DA, Joe PA, Hopper-Borge E, Luduena RF, Kruh GD, Mooberry SL. The taccolonides: microtubule stabilizers that circumvent clinically relevant taxane resistant mechanisms. Cancer Res. 2008;68:8881-88. PubMed
7. Hopper-Borge E, Chen Z-S, Shchaveleva I, Belinsky MG, Kruh GD. Analysis of the drug resistance profile of MRP7 (ABCC10): resistance to docetaxel. Cancer Res. 2004;64:4927-30. PubMed
8. Hopper E, Belinsky M, Zeng H, Tosolini A, Testa J, Kruh G. Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily. Cancer Letters. 2001;162:181-191. PubMed

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The Role of Protein Quaternary Structure in the Control of Function

The Jaffe laboratory studies protein structure-function relationships using both biochemical and biophysical approaches. We have recently become focused on the roles of protein quaternary structure dynamics in the control of protein function. This follows our discovery that at least one homo-oligomeric protein can dissociate, the dissociated units can change conformation, and these altered conformations support association to a structurally and functionally distinct oligomeric assembly. Unlike the prion phenomenon, our characterized changes in subunit structure are subtle, the oligomeric stoichiometry is finite, and the process is freely reversible. We have associated this structural dynamic with allosteric regulation of protein function, with human disease, and with new opportunities for allosteric drug discovery. The now well established structural dynamic was originally unexpected and we were reticent to accept its validity. However, realizing the novelty of this discovery, we coined the term morpheein to describe proteins that could reversibly dissociate, change conformation, and assemble differently with finite stoichiometry. What we have learned from the prototype morpheein allows us to mine the literature and protein structure databases in search of other proteins that function as morpheeins. We have identified a family of putative morpheeins, many of which can be approached as drug targets, including cancer chemotherapeutic targets.

Selected Publications

1. Selwood T, Jaffe EK. Dynamic dissociating homo-oligomers and the control of protein function. Arch Biochem Biophys. 2012 Mar 15;519(2):131-43. PubMed
2. Jaffe EK, Lawrence SH. Allostery and the dynamic multimerization of porphobilinogen synthase. Arch Biochem Biophys. 2012;519:144-53. PubMed
3. Lawrence SH, Selwood T, Jaffe EK. Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme. ChemMedChem. 2011 Jun 6;6(6):1067-73. doi: 10.1002/cmdc.201100009. PubMed
4. Jaffe EK, Shanmugan D, Gardberg A, Dieterich M, Banumathi S, Stewart LJ, Myler PJ, Roos DS. Crystal structure of Toxoplasma gondii porphobilinogen synthase: Insight on octameric structure and porphobilinogen formation. J Biol Chem. 2011 Mar 7. PubMed
5. Jaffe EK. Morpheeins, a new pathway for allosteric drug discovery. Open Conf Proc J. 2010;1:1-6. PubMed
6. Shanmugam D, Wu B, Ramirez U, Jaffe EK, Roos DS. Plastid-associated porphobilinogen synthase from Toxoplasma gondii: kinetic and structural properties validate therapeutic potential. J Biol Chem. 2010 Jul 16;285(29):22122-31. PubMed
7. Lawrence SH, Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK. Shape shifting leads to small-molecule allosteric drug discovery. Chem Biol. 2008;15:586-96. PubMed
8. Jaffe EK, Stith L. ALAD Porphyria Is a Conformational Disease. Am J Hum Genet. 2007 80:329-37. PubMed
9. Tang L, Breinig S, Stith L, Mischel A, Tannir J, Kokona B, Fairman R, Jaffe EK. Single amino acid mutations alter the distribution of human porphobilinogen synthase quaternary structure isoforms (morpheeins). J Biol Chem. 2006 281:6682-90. PubMed
10. Jaffe EK. Morpheeins - a new structural paradigm for allosteric regulation. Trends Biochem Sci. 2005;30:490-7. PubMed

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Development and Implementation of Advanced Beam Modalities and Treatment Techniques for Radiation Cancer Therapy

Current research from the Radiation Physics department includes: Radiation dosimetry, dose calculation algorithms, Monte Carlo simulation techniques; Intensity-modulated radiation therapy (IMRT), treatment optimization, beam delivery, dose verification; Modulated electron radiation therapy (MERT), treatment planning, beam delivery and dose verification; Real-time, image-guided robotic radiosurgery/therapy, plan optimization and beam delivery; Laser-accelerated proton beams for radiotherapy, particle-in-cell (PIC) simulations, target design, Particle selection and collimation system, proton dose calculation, plan optimization and beam delivery.

Selected Publications

1. Ma C-M, Li JS, Deng J and Fan J. Implementation of Monte Carlo Dose Calculation for CyberKnife treatment planning, Journal of Physics: Conference Series 2008;102:012-016.
2. Ma, C-M and Paskalev, K. In-Room CT Techniques for Image-Guided Radiation Therapy. Med Dosimetry 2006;31:30-39.PubMed
3. Ma C-M, Maughan R, Orton C. Within the next decade conventional cyclotrons for proton radiotherapy will become obsolete and replaced by far less expensive machines using compact laser systems for the acceleration of the protons. Med Phys. 2006;33:571-73. PubMed
4. Ma C-M, Ding M, Li JS, Lee MC, Pawlicki T, Deng J. A Comparative Dosimetric Study on Tangential Photon Beams, IMRT and MERT for Breast Cancer Treatment, Phys Med Biol. 2003;48:909-24. PubMed
5. Ma, C-M, Liu C, Coffey C, Nath R, Seltzer S, Seuntjens J. AAPM protocol for 40-300kV x-ray beam dosimetry for radiotherapy and radiobiology. Med Phys. 2001;28:868-893. PubMed

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Research Interests

The clinical trials available at Fox Chase give patients access to more treatment options and the hope of improving cancer treatment for future patients. I have a special interest in targeted-therapies, which have become important to the future of cancer treatment. These therapies have the potential to reduce toxic side effects and improve control of disease. Specific areas of research interest include the clinical management of melanoma, and of gynecological cancers such as ovarian cancer.  In contrast to breast cancer, which often responds well to treatment and yields a complete cure, ovarian cancer typically recurs in a form resistant to initial treatment.  My work is directed both at finding treatments that are effective in increasing survival, and also at providing better palliative care.

Selected Publications

1. Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M, Yala S, Kanteti R, Cohen EEW, Lingen MW, Martin L, Krishnaswamy S, Klein-Szanto A, Christensen JG, Vokes EE, Salgia R. The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009;69:3021-3031.
2. Martin LP, Schilder RJ. Management of recurrent ovarian carcinoma: current status and future directions. Semin Oncol. 2009;36:112-125.
3. Martin LP, Hamilton TC, Schilder RJ. Platinum resistance: The role of DNA repair pathways. Clin Cancer Res. 2008;14:1291-1295. Accepted prior to April 7, 2008
4. Martin L, Schilder R. Novel approaches in advancing the treatment of epithelial ovarian cancer: the role of angiogenesis inhibition. J Clin Oncol. 2007;25:2894-2901.
5. Martin LP, Schilder RJ. The role of pertuzumab in ovarian cancer: Phase I development and preclinical rationale. Physician's Education Resource. Targeted Therapies in Oncology 2006 Mar;5(1).
6. Martin L, Schilder RJ. Novel non-cytotoxic therapy in ovarian cancer: Current status and future prospects. J Natl Compr Canc Netw. 2006;4:955-966.
7. Martin L, Schilder RJ. Front-line treatment of epithelial ovarian cancer: Focus on the medical oncologists' perspective. Am J Cancer. 2005;4:221-231.
8. Martin L, Schilder RJ. Front-line treatment of epithelial ovarian cancer: Focus on the medical oncologists' perspective. Am J Cancer. 2005;4:221-231.

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Research Interests

My research seeks to improve clinical management of head and neck cancers, with a main research focus of bringing novel targeted therapies into the clinic.  Substantial evidence is now available for head and neck cancers and for other cancers indicating that high protein expression of ERCC1, a gene that takes part in the cellular response to DNA damage, predicts resistance to the common therapeutic agent cisplatin. An important goal in personalizing therapy in head and neck cancer is to establish whether ERCC1-guided therapy can spare certain patients the toxicity of high dose cisplatin treatment, while maintaining or improving on patient outcomes. I am collaborating with Fox Chase faculty to utilize highly quantitative immunofluorescence (AQUA) in situ proteomics to demonstrate the range of ERCC1 expression in head and neck cancers, to help identify patients for specific treatment regimens.  DNA-directed treatments such as cisplatin are often used together with radiation therapy and targeted therapies such as blockade of proteins that contribute to tumor growth, such as the epidermal growth factor receptor (EGFR).  I also collaborate with a number of colleagues performing clinical and basic research at Fox Chase to analyze the best use of cetuximab, an antibody that blocks signaling by EGFR, in recurrent and/or metastatic head and neck cancers.

Another research focus of mine is to improve the treatment of thoracicmalignancies, again with the study of targeted agents for the treatment of lung cancer.  I am the principal investigator of a trial to study the agent vorinostat for the treatment of locally advanced non-small cell lung cancer. I also am working with other Fox Chase investigators to evaluate the presence of circulating tumor cells in patients with lung cancer.

Selected Publications

1. Andrews G, Lango M, Cohen R, Feigenberg S, Burtness B, Mehra R, Ahmed S, Nicolaou N, Gaughan J, Ridge JA. Non-surgical management of oropharyngeal, laryngeal and hypopharyngeal cancer: the Fox Chase Cancer Center experience. Head Neck, in press, 2010.
2. Rusthoven KE, Feigenberg SJ, Raben D, Kane M, Song JI, Nicolaou N, Mehra R, Burtness B, Ridge J, Swing R, Lango M, Cohen R, Jimeno A, Chen C. Initial results of a phase I dose-escalation trial of concurrent and maintenance erlotinib and reirradiation for recurrent and new primary head and neck cancer. Int J Radiat Oncol Biol Phys. 2010;78:1020-1025.
3. Turaka A, Li T, Sharma NK, Li L, Nicolaou N, Mehra R, Burtness B, Cohen RB, Lango MN, Horwitz EM, Ridge JA, Feigenberg SJ. Increased recurrences using intensity-modulated radiation therapy in the postoperative setting. Am J Clin Oncol. 2010 Dec;33(6):599-603.
4. Burtness B, Gibson M, Egleston B, Mehra R, Thomas L, Sipples R, Quintanilla M, Lacy J, Watkins S, Murren JR, Forastiere AA. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-8.
5. Borghaei H, Mehra R, Simon G. Current issues in adjuvant chemotherapy for resected, stage IB non-small-cell lung cancer. Fut Oncol. 2009;5:19-22.
6. Mehra R, Treat J. Part II: Treatment of non-small-cell lung cancer: chemotherapy. In: Fishman's Pulmonary Diseases and Disorders (Fishman, A.P., Elias, J.A., eds.), 4th ed., pp. 1867-1882. McGraw-Hill, Medical Publishing Division, NY, 2008. Book Chapter
7. Mehra R, Cohen RB, Harari P. Targeted therapies in head and neck cancer. In: Combining Targeted Biological Agents With Radiotherapy: Current Status and Future Directions (Small, W., ed.), pp. 107-138. Demos Medical Publishers, NY, 2008. Book Chapter
8. Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol. 2008;6:742-750.
9. Mehra R, Cohen RB. New agents in the treatment for malignancies of the salivary and thyroid glands. Hematol Oncol Clin North Am. 2008;22:1279-1295.
10. Mehra R, Burtness B. Antibody therapy for early-stage breast cancer: trastuzumab adjuvant and neoadjuvant trials. Expert Opin Biol. 2006;Ther. 6:951-962.

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Research Interests

Research in Gynecologic Oncology at Fox Chase is a multidisciplinary effort with an emphasis on the translation of basic science discoveries to clinical trials and patient care.  I collaborate with Dr. Paul Cairns on a project in our Ovarian Cancer SPORE exploring the role of epigenetic modification of genes in cancer development, prognosis and response to treatment. I am the principal investigator for clinical trials of the Gynecologic Oncology Group (GOG) and sit on the GOG’s developmental therapeutics and ovarian cancer committees. Working through the GOG, I am the principal investigator of an international clinical trial evaluating intraperitoneal chemotherapy combined with anti-angiogenesis therapy in the treatment of ovarian cancer.  In addition, as Chief of the Division of Gynecologic Oncology, our surgeons are often responsible for securing tumor tissue for Fox Chase’s Biosample Repository which supports basic research here and throughout the country.  We also collaborate with the Department of Cancer Prevention and Control, studying the role of stress on the immune response to the human papilloma virus (HPV),  psychotherapy in coping with the diagnosis and treatment of ovarian cancer and novel ways of addressing the needs of women at risk for developing gynecologic cancers.

Selected Publications

1. Morgan MA, Sill MW, Fujiwara K, Greer B, Rubin SC, DeGeest K, Yamada SD, Waggoner S, Coleman RL, Walker JL, Mannel RS. A phase I study with an expanded cohort to asses the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group Study. Submitted 2010.
2. Morgan MA, Polan ML, Melecot HH, Debru B, Sleemi A, Husain A. Experience with a low-pressure colonic pouch (Mainz II) urinary diversion for irreparable vesicovaginal fistula and bladder extrophy in East Africa. Int Urogynecol J, 2009 October; 20:1163-1168. PubMed
3. Greer BE, Koh WJ, Abu-Rustum N, Bookman, MA, Bristow RE, Campos SM, Cho,KR, Copeland L, Crispens MA, Eifel PJ, Huh WK, Jagernauth W, Kapp DS, Kavanagh JJ, Lurain JR 3rd, Morgan MA, Morgan RJ, Powell CB, Remmenga SW, Reynolds RK, Alvarez Secord A, Small W Jr., Teng N. NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. J Natl Compr Canc Netw, 2009 May;7(5):498-531.
4. Novi JM, Mulvihill BHK, Morgan, MA. Combined Anal Sphincteroplasty and Perineal Reconstruction for Fecal Incontinence in Women. JAOA, 2009 April;109, 4:234-236
5. Morgan MA, Darcy KM, Rose PG, DeGeest K, Bookman MA, Aikins JK, Sill MW, Mannel RS, Allievi C, Egorin MJ. Paclitaxel poliglumex and carboplatin as first-line therapy in ovarian, peritoneal or fallopian tube cancer: A phase I and feasibility trial of the Gynecologic Oncology Group. Gynecologic Oncology 2008;110:329-335. PubMed
6. Morgan, M. Intraperitoneal chemotherapy for ovarian cancer. Adv Exp Med Biol. 2008;622:145-51. PubMed
7. Morgan, M. The main site of origin for malignancies detected during risk- reducing surgery for ovarian cancer. Nat Clin Pract Oncol. 2008 March; 5(3):134-5. PubMed
8. Partridge EE, Abu-Rustum N, Campos S, Fahey PJ, Greer BE, Lele SM, Lieberman RW, Lipscomb GH, Morgan M, Nava ME, Reynolds RK, Singh DK, Smith-McCune K, Teng N, Trimble CL, Valea F, Wilczynski S. Cervical cancer screening. J Natl Compr Canc Netw. 2008 Jan;6(1):58-82. PubMed
9. Greer BE, Koh WJ, Abu-Rustum N, Bookman MA, Bristow RE, Campos S, Cho KR, Copeland L, Eifel P, Huh WK, Jaggernauth W, Kapp DS, Kavanagh J, Lipscomb GH, Lurain JR 3rd, Morgan M, Morgan RJ Jr, Powell CB, Remmenga SW, Reynolds RK, Secord AA, Small W Jr, Teng N; National Comprehensive Cancer Network. Cervical cancer. J Natl Compr Canc Netw. 2008 Jan;6(1):14-36. PubMed
10. Kavanagh JJ, Sill MW, Ramirez PT, Warshal D, Pearl ML, Morgan MA. Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: A Gynecologic Oncology Group Study. Int J Gynecol Cancer. 2008 May-Jun;18(3):460-4. PubMed
11. Novi JM, Bradley CS, Mahmoud NN, Morgan MA, Arya LA. Sexual function in women after rectocele repair with acellular porcine dermis graft vs site-specific rectovaginal fascia repair. Int Urogynecol J Pelvic Floor Dysfunct. 2007 Oct;18(10):1163-9. PubMed
12. Srinivasan R, Yang Y, Rubin, SC, Morgan, MA, Lewis, JD. Risk of colorectal cancer in women with a prior diagnosis of gynecologic malignancy. J Clin Gastroenterol. 2007 Mar;41(3):291-6. PubMed
13. Fujiwara K, Armstrong D, Morgan M, Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer. 2007 Jan-Feb;17(1):1-20. PubMed
14. Brewer CA, Blessing JA, Nagourney RA, Morgan MA, Hanjani P. Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2006 Nov;103(2):446-50. PubMed

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Research Summary

Dr. Olszanski’s research focus is principally aimed at developing new drugs through collaborations with investigators, cooperative groups, and pharmaceutical companies. His greatest interest lies in early drug development (Phase 1 Research Trials) using molecularly targeted small molecules or antibodies in cancer. Through the collaborative efforts of the Developmental Therapeutics Program he focuses on the development of biomarkers to help define the optimal patient population who will benefit from a new drug. “Clinical trials often offer patients new drugs that are not yet available, and they continue to drive our understanding of cancer, leading to improved therapies. I try to offer my patients a clinical trial whenever feasible as I feel that the care that takes place on a trial is often better than one receives off trial,” Olszanski maintains.

In addition to his interests in early drug development, Dr. Olszanski specializes in the treatment of melanoma and gastrointestinal malignancies. “The [melanoma] field is very exciting right now because of the emergence of new targeted therapies that are really impacting this disease. These are the first advances after decades of research. Unfortunately, some patient’s tumors develop resistance to these new therapies. Understanding drug-resistance is a pivotal focus of the Developmental Therapeutics Program”

Selected Publications

1. Rini BI, Schiller JH, Fruehauf J et al. and Olszanski AJ, Diastolic Blood Pressure as a Biomarker of Axitinib Efficacy. Lancet Oncology. In press.
2. Michael M, Vlahovic G, Khamly K, Pierce KJ, Guo F, Olszanski AJ. Phase Ib study of CP-868,596, a PDGFR inhibitor, in combination with docetaxel with or without axitinib, a VEGFR inhibitor. Br J Cancer. 2010 Nov 9;103(10):1554-61. PubMed
3. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J. Efficacy and Safety of Axitinib in Patients with Advanced Non-Small Cell Lung Cancer: Results from a Phase II Study. J Clin Oncol. 2009 Aug 10;27(23):3836-41. PubMed
4. Lewis NL, Lewis LD, Eder JP, Reddy NJ, Guo F, Pierce KJ, Olszanski AJ, Cohen RB. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific PDGFR tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol. 2009 Nov 1;27(31):5262-9. PubMed
5. Mita AC, Olszanski AJ, Walovitch RC, Perez RP, MacKay K, Tuck DP, Simmons C, Hammond S, Mita MM, Beeram M, Stone AJ, Rowinsky EK, Lewis LD. Phase I and Pharmacokinetic Study of AI-850, A Novel Microparticle Hydrophobic Drug Delivery System for Paclitaxel. Clin Cancer Res. 2007 Jun 1;13(11):3293-301. PubMed
6. Perez RP, Lewis LD, Beelen AP, Olszanski AJ, Johnston N, Rhodes CH, Beaulieu B, Ernstoff MS, Eastman A. Modulation of Cell-cycle Progression in Human Tumors: A Pharmacokinetic and Tumor Molecular Pharmacodynamic Study of Cisplatin Plus the Chk1 Inhibitor UCN-01. Clin Cancer Res. 2006 Dec 1;12(23):7079-85. PubMed

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Research Interests

Most of my research in the last 15 years has been undertaken at a national level, and has involved the design and execution of clinical trials. With the recent marshaling of Fox Chase Cancer Center patient care and scientific strengths to address Head & Neck cancer, I have formally joined the Developmental Therapeutics Program. I am able to provide an important clinical context for research, promote translational goals (with patients and physician colleagues), and link with clinicians in other fields. The science is fascinating, and relevant to my background in structural biology. I anticipate an exciting a fruitful collaboration.

Selected Publications

1. Andrews G, Lango M, Cohen R, Feigenberg S, Burtness B, Mehra R, Ahmed S, Nicolaou N, Gaughan J, Ridge JA. Non-surgical management of oropharyngeal, laryngeal and hypopharyngeal cancer: the Fox Chase Cancer Center experience. Head Neck, in press, 2010.
2. Rusthoven KE, Feigenberg SJ, Raben D, Kane M, Song JI, Nicolaou N, Mehra R, Burtness B, Ridge J, Swing R, Lango M, Cohen R, Jimeno A, Chen C. Initial results of a phase I dose-escalation trial of concurrent and maintenance erlotinib and reirradiation for recurrent and new primary head and neck cancer. Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1020-5.
3. Turaka A, Li T, Yu JQ, Nicolaou N, Burtness B, Lango MN, Ridge JA, Feigenberg SJ. Intensity Modulated Radiation Therapy (IMRT) for thyroid vancer. 2010;Thyroid Sci. 5:CLS1-5, 2010.
4. Turaka A, Li T, Nicolaou N, Lango MN, Burtness B, Horwitz EM, Ridge JA, Feigenberg SJ. Use of a conventional Low Neck Field (LNF) and Intensity-Modulated Radiotherapy (IMRT): no clinical detriment of IMRT to an anterior LNF During the treatment of head-and neck-cancer. Int J Radiat Oncol Biol Phys. 2010 Apr 10.
5. Turaka A, Li T, Sharma NK, Li L, Nicolaou N, Mehra R, Burtness B, Cohen RB, Lango MN, Horwitz EM, Ridge JA, Feigenberg SJ. Increased recurrences using intensity-modulated radiation therapy in the postoperative setting. Am J Clin Oncol. 2009 Dec 30
6. Martinez E, Tatum KL, Weber DM, Kuzla N, Pendley A, Campbell K, Ridge JA, Langer C, Miyamoto C, Schnoll RA. Issues related to implementing a smoking cessation clinical trial for cancer patients. Cancer Causes Control. 2009 Feb;20(1):97-104.
7. Lango MN, Andrews GA, Ahmad S, Feigenberg S, Tuluc M, Gaughan J, Ridge JA. Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathological residual carcinoma and prognosis. Head Neck. 2009 Mar;31(3):328-37.
8. National Comprehensive Cancer Network, Forastiere AA, Ang KK, Brizel D, Brockstein BE, Burtness BA, Cmelak AJ, Colevas AD, Dunphy F, Eisele DW, Goepfert H, Hicks WL Jr, Kies MS, Lydiatt WM, Maghami E, Martins R, McCaffrey T, Mittal BB, Pfister DG, Pinto HA, Posner MR, Ridge JA, Samant S, Schuller DE, Shah JP, Spencer S, Trotti A 3rd, Weber RS, Wolf GT, Worden F. Head and neck cancers. J Natl Compr Canc Netw. 2008 Aug;6(7):646-95.
9. Brown KM, Lango M, Ridge, J.A. The role of neck dissection in the combined modality therapy setting. Semin Oncol. 2008;35:229-35.
10. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008 Feb 20;100(4):261-9.
11. Willis AI, Ridge JA. Discordant lymphatic drainage patterns revealed by serial lymphoscintigraphy in cutaneous head and neck malignancies. Head Neck. 2007;29:979-985.
12. Feigenberg SJ, Lango M, Nicolaou N, Ridge JA. Intensity-modulated radiotherapy for early larynx cancer: is there a role? Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):2-3.
13. Trotti, A., Pajak, T.F., Gwede, C.K., Paulus, R., Cooper, J., Forastiere, A., Ridge JA, Watkins-Bruner, D., Garden, A.S., Ang, K.K., Curran, W. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 8:613-624, 2007.
14. Kell MR, Ridge JA, Joseph N, Sigurdson ER. PET CT imaging in patients undergoing sentinel node biopsy for melanoma. Eur J Surg Oncol. 2007 Sep;33(7):911-3.
15. Ro EY, Ridge JA, Topham NS. Using stereolithographic models to plan mandibular reconstruction for advanced oral cavity cancer. Laryngoscope. 2007 Apr;117(4):759-61.
16. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, Ridge JA, Goodwin J, Kenady D, Saunders J, Westra W, Sidransky D, Koch WM. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007 Dec 20;357(25):2552-61.
17. Pfister DG, Ridge JA. Induction chemotherapy for larynx preservation: Patient selection or therapeutic effect? J Clin Oncol. 2006 Feb 1;24(4):540-3.
18. Langer CJ, Duffy K, Horwitz EM, Litwin S, Rosvold E, Schol J, Keenan E, Nicolaou N, Friedman CD, Ridge JA. Phase I trial of concurrent hyperfractionated split course radiotherapy (HFx RT), cisplatin (cDDP), and paclitaxel in patients with recurrent, previously irradiated, or treatment-naive locally advanced upper aerodigestive malignancy. Cancer Invest. 2006 Mar;24(2):164-73.
19. Siegelmann-Danieli N, Ben-Izhack O, Hanlon A, Ridge JA, Stein ME, Khandelwal V, Langer CJ. P53 alteration in oral tongue cancer is not significantly associated with age at diagnosis or tobacco exposure. Tumori. 2005;91:346-50.
20. Schnoll RA, Rothman RL, Wielt DB, Lerman C, Pedri H, Wang H, Babb J, Miller SM, Movsas B, Sherman E, Ridge JA, Unger M, Langer C, Goldberg M, Scott W, Cheng J. A randomized pilot study of cognitive-behavioral therapy versus basic health education for smoking cessation among cancer patients. Ann Behav Med. 2005 Aug;30(1):1-11.
21. Kramer NM, Horwitz EM, Cheng J, Ridge JA, Feigenberg SJ, Cohen RB, Nicolaou N, Sherman EJ, Babb JS, Damsker JA, Langer CJ. Toxicity and outcome analysis of patients with recurrent head and neck cancer treated with hyperfractionated split-course reirradiation and concurrent cisplatln and paclitaxel chemotherapy from two prospective Phase I and II studies. Head Neck. 2005 May;27(5):406-14.
22. Ridge JA, Glisson BS, Horwitz E, Lango M. Head and neck cancer. In: Cancer Management: A Multidisciplinary Approach (Pazdur, R., Coia, L.R., Hoskins, W.J., Wagman, L.D., eds.), pp. 43-90. CMP Healthcare Media, Manhasset, 2005.
23. Henry LR, Ridge JA. Parotidectomy. In: ACS Surgery Principles & Practice (Souba, W.W., Fink, M.P., Jurkovich, L.R., Kaiswer, W.H., Pearce, J.H., Pemberton, N.J., Soper, N.J., eds.), pp. 176-184. Web MD Inc., NY, 2005.

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Engineered Antibodies as Cancer Diagnostic and Therapeutic Agents

As researchers have learned more about the mechanisms that initiate cancer and drive its progression, they have pioneered targeted drug and antibody therapies that are capable of disrupting these mechanisms. These therapies have benefited patients with a variety of cancers, but the targeted tumor cells almost invariably develop resistance to the treatments.

Our laboratory focuses on using antibody-engineering techniques to design antibodies for the purpose of diagnosing or treating cancer. We use rational design methods to build antibodies that match the structure of proteins found on the surface of tumor cells. In this way, we increase the antibodies’ efficacy by improving their ability to selectively target tumor cells. We are also working on understanding both how resistance to targeted drugs arises and how the antibodies we are developing can be exploited to overcome drug resistance.

Selected Publications

1. Reddy S, Shaller CC, Doss M, Shchaveleva I, Marks JD, Yu JQ, Robinson MK, Evaluation of the anti-HER2 C6.5 diabody as a PET radiotracer to monitor HER2 status and predict response to trastuzumab treatment. Clin Cancer Res. (in press)
2. Reddy S, Robinson MK, Immuno-Positron Emission Tomography in Cancer Models. Semin Nucl Med. 2010 May 40:182-189. Epub 2010 Mar 31. PubMed
3. Robinson MK, Alpaugh RK, Borghaei H. Naptumomab estafenatox: a new immunoconjugate. Expt Opin Biol Ther. 2010 Feb 10(2):273-279. Epub 2010 Jan 8. PubMed
4. Robinson MK, Hodge KM, Horak E, Sundberg AL, Russeva M, Shaller CC, Simmons HH, Von Mehren M, Shchaveleva I, Marks JD, Adams GP. Targeting ErbB2 and ErbB3 with a bispecific-single chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. Br J Cancer. 2008 Nov 4;99(9):1415-25. Epub 2008 Oct 7. PubMed
5. Robinson MK, Shaller C, Garmestani K, Plascjak PS, Hodge KM, Yuan QA, Marks JD, Waldmann TA, Brechbiel MW, Adams GP. Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the a-emitting radioisotope astatine-211 conjugated to anti-HER2 /neu diabodies. Clin Cancer Res. 2008 Feb 1;14(3):875-82. PubMed
6. Robinson MK, Borghaei H, Adams GP, Weiner LM. Pharmacology of cancer biotherapeutics – monoclonal antibodies. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology, 8th edition. Lippincott, Williams & Wilkins;2008. p. 537-47.
7. Robinson MK, Doss M, Shaller C, Narayanan D, Marks J, Adler LP, Gonzalez Trotter DE, Adams GP. Quantitative immunoPET imaging of HER2-positive tumor xenografts with an iodine-124 labeled anti-HER2 diabody. Cancer Res. 2005 Feb 15;65(4):1471-8. PubMed

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Protein Folding, Structure and Function

A central theme of our research concerns the early stages of protein folding, which are critical for understanding how the native structure of a protein, and ultimately its function, are encoded in the amino acid sequence. The insight gained not only provides a basis for protein structure prediction and de novo design, but also contributes to our mechanistic understanding and treatment of a wide range of diseases that involve aggregation of denatured or misfolded proteins. The stability and folding dynamics of proteins also has major implications with respect to understanding of the physiological consequences of mutations, in vivo folding and other cellular processes, such as trafficking and degradation. We study the dynamics of protein folding on a microsecond time scale by coupling advanced mixing techniques with various detection methods, including fluorescence and H/D exchange labeling experiments with NMR detection. In combination with protein engineering, these approaches have provided detailed insight into the folding mechanisms of a diverse set of proteins [reviewed in Roder et al, 2006]. A novel quenched-flow H/D exchange method is now being used to detect the formation of individual hydrogen bonds in early folding intermediates of cytochrome c and staphylococcal nuclease, which accumulate in less than 100 μs. The results indicate that the initial compaction of the protein involves specific formation of secondary and tertiary structure rather than a non-specific hydrophobic collapse.

Our group also investigates the structure, dynamics and molecular interactions of various proteins of biomedical interest in solution by using NMR spectroscopy and other biophysical methods. In collaboration with Peter N. Walsh at Temple University we recently showed that zymogen activation of factor XI (triggered by cleavage of a scissile bond) is accompanied by a major change in overall shape of this large multi-domain protein [Samuel et al, 2007]. The findings serve as a paradigm for understanding the role of protein structural rearrangements in regulating protein interactions and enzymatic activity. Other studies focus on the signaling adaptor protein Na+/H+ exchanger regulatory factor 1 (NHERF1), which plays a central role in cellular pathways relating receptors and ion channels with the actin cytoskeleton. NHERF1 contains two globular domains belonging to the PDZ domain family and a C-terminal ezrin binding (EB) motif, as well as two long segments predicted to be intrinsically disordered. We have recently shown, using NMR, circular dichroism and fluorescence methods, that NHERF1 can assume two alternative closed conformations in which the second PDZ domain engages the C-terminal region via eith non-specific interactions with the disordered linker or specific contacts with the EB motif [Cheng et al., 2009]. The initially unstructured EB region becomes helical when bound to the second PDZ domain. Together with equilibrium unfolding and ligand binding data, the findings indicate that the activity of NHERF as a signaling adaptor is regulated by a subtle balance between competing intra- and intermolecular domain-domain interactions.

Selected Publications

1. Xu M, Beresneva O, Rosario R, Roder H. Microsecond Folding Dynamics of Apomyoglobin at Acidic pH. J Phys Chem B. 2012; 116(23):7014-25. PubMed
2. Korendovych I V, Kulp DW, Wu Y, Cheng H, Roder H, DeGrado WF. Design of a switchable eliminase. Proc Natl Acad Sci U S A. 2011;108:6823-7. PubMed
3. Chen KC, Xu M, Wedemeyer WJ, Roder H. Microsecond unfolding kinetics of sheep prion protein reveals an intermediate that correlates with susceptibility to classical scrapie. Biophys J. 2011;101:1221-30. PubMed
4. Lau WL, DeGrado WF, Roder H. The effects of pKa tuning on the thermodynamics and kinetics of folding: Design of a solvent-shielded carboxylate pair at the “a”position of a coiled coil. Biophys J. 2010; 99:2299-2308. PubMed
5. Alves C, Cheng H, Roder H, Taylor J. Intrinsic disorder and oligomerization of the hepatitis delta virus antigen. Virology. 2010; 407:333-340. PubMed
6. Cheng H, Li J, Fazlieva R, Dai Z, Bu Z, Roder H. Autoinhibitory interactions between the PDZ2 and C-terminal domains in the scaffolding protein NHERF1. Structure. 2009;17(5):660-669. PubMed
7. Latypov RF, Maki K, Cheng H, Luck SD, Roder H. Folding mechanism of reduced Cytochrome c: equilibrium and kinetic properties in the presence of carbon monoxide. J Mol Biol. 2008;383(2):437-53. PubMed
8. Maki K, Cheng H, Dolgikh DA, Roder H. Folding kinetics of staphylococcal nuclease studied by tryptophan engineering and rapid mixing methods. J Mol Biol. 2007;368(1):244-55. PubMed
9. Samuel D, Cheng H, Riley PW, Canutescu AA, Nagaswami C, Weisel JW, Bu Z, Walsh PN, Roder H. Solution structure of the A4 domain of factor XI sheds light on the mechanism of zymogen activation. Proc Natl Acad Sci USA. 2007;104(40):15693-8. PubMed
10. Apetri AC, Maki K, Roder H, Surewicz WK. Early intermediate in human prion protein folding as evidenced by ultrarapid mixing experiments. J Am Chem Soc. 2006;128(35):11673-8. PubMed
11. Latypov RF, Cheng H, Roder NA, Zhang J, Roder H. Structural characterization of an equilibrium unfolding intermediate in cytochrome c. J Mol Biol. 2006;357(3):1009-25. PubMed
12. Roder H, Maki K, Cheng H. Early events in protein folding explored by rapid mixing methods. Chem Rev. 2006;106(5):1836-61. PubMed
13. Kuwata K, Matumoto T, Cheng H, Nagayama K, James TL, Roder H. NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126. Proc. Natl Acad Sci USA. 2003;100(25):14790-5. PubMed

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Research Interests

My research efforts in two areas. First, I work closely with the Chief Scientific Officer and the Executive Committee of Research to build stronger collaborative scientific efforts through the strategic investment of Center resources to enhance team based science. In addition, I continue my efforts to explore translational research strategies in the management of women with ovarian cancer. Specifically, I serve as the Principal Investigator for the Fox Chase Cancer
Center/University of Pennsylvania Ovarian SPORE Grant. This grant supports five research projects and numerous smaller pilot studies exploring various options for improving the outcome of women with ovarian cancer or at increased lifetime risk of developing ovarian cancer.

Selected Publications

1. Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, Roberts DJ, Seiden MV, Scadden DT, Rueda BR, Foster R. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009 Dec;27(12):2875-83.
2. del Carmen MG, Findley Muzikansky MA, Roche M, Verrill CL, Horowitz N, Seiden MV. A comparison of demographics, risk factors, and screening knowledge between Latino and non-Latino women referred for colposcopy. Gynecol Oncol. 2007;104:70-76.
3. Hesterberg PE, Banerji A, Oren E, Penson RT, Krasner CN, Seiden MV, Wong JT. Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management. J Allergy Clin Immunol. 2009 Jun;123(6):1262-7.e1.
4. Seiden MV. (Editor). Progress in gynecologic cancer. Semin Oncol. 2009;36:90.
5. Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 2008 May 15;14(10):3193-203. Accepted prior to April 7, 2008
6. Duan Z, Ames RY, Ryan M, Hornicek FJ, Mankin H, Seiden MV. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells. Cancer Chemother Pharmacol. 2009 Mar;63(4):681-9. Epub 2008 Jun 28.
7. van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MM. Biodistribution and pharmacokinetic analysis of paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model. Mol Pharm. 2008 Jul-Aug;5(4):516-26. Epub 2008 Jul 11.
8. Growden WB, Lopez-Varela E, Littell R, Oliva E, Seiden M, Krasner C, Lee H, Fuller A. Extent of extracranial disease is a powerful predictor of survival in patients with brain metastases from gynecologic cancer. Int J Gynecol Cancer. 2008;18:262-268. Accepted prior to April 7, 2008
9. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10. Epub 2008 Feb 19.
10. Sakamoto H, Friel AM, Wood AW, Guo L, Ilic A, Seiden MV, Chung DC, Lynch MP, Serikawa T, Munro E, Oliva E, Orsulic S, Kirley SD, Foster R, Zukerberg LR, Rueda BR. Mechanisms of cables 1 gene inactivation in human ovarian cancer development. Cancer Biol Ther. 2008 Feb;7(2):180-88. Epub 2007 Nov 15.
11. Lenzi R, Edwards R, June C, Seiden MV, Garcia ME, Rosenblum M, Freedman RS. Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1 cm) associated with ovarian cancer or primary peritoneal carcinoma. J Transl Med. 2007 Dec 12;5:66.
12. Berkenblit A, Eder JP Jr, Ryan DP, Seiden MV, Tatsuta N, Sherman ML, Dahl TA, Dezube BJ, Supko JG. Phase I clinical trial of STA-4783 in combination with Paclitaxel in patients with refractory solid tumors. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):584-90.
13. Duan Z, Bradner J, Greenberg E, Mazitschek R, Foster R, Mahoney J, Seiden MV. 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008), a novel janus kinase 2 inhibitor, increases chemotherapy sensitivity in human ovarian cancer cells. Mol Pharmacol. 2007 Nov;72(5):1137-45. Epub 2007 Aug 3.
14. Devalapally H, Duan Z, Seiden MV, Amiji MM. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int J Cancer. 2007 Oct 15;121(8):1830-8.
15. Oei AL, Verheijen RH, Seiden MV, Benigno BB, Lopes A, Soper JT, Epenetos AA, Massuger LF. Decreased intraperitoneal disease recurrence in epithelial ovarian cancer patients receiving intraperitoneal consolidation treatment with yttrium-90-labeled murine HMFG1 without improvement in overall survival. Int J Cancer. 2007 Jun 15;120(12):2710-4.
16. van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Augmentation of therapeutic efficacy in drug-resistant tumor models using ceramide coadministration in temporal-controlled polymer-blend nanoparticle delivery systems. Cancer Res. 2007 May 15;67(10):4843-50.
17. Seiden MV, Burris HA, Matulonis U, Hall JB, Armstrong DK, Speyer J, Weber JD, Muggia F. A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody in patients with platinum resistant ovarian and primary peritoneal malignancies. Gynecol Oncol. 2007 Mar;104(3):727-31. Epub 2006 Nov 28.
18. Skates SJ, Horick NK, Moy JM, Minihan AM, Seiden MV, Marks JR, Sluss P, Cramer DW. Pooling of case specimens to create standard serum sets for screening cancer biomarkers. Cancer Epidemiol Biomarkers Prev. 2007 Feb;16(2):334-41.
19. van Vlerken, L.E., Duan, Z., Seiden, M.V., Mansoor, M., Amiji, M.M. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multi-drug resistance in tumor cells. Cancer Res. 67:4843-4850, 2007.
20. Seiden MV, Patel D, O'Neill MJ, Oliva E. Case Reports of the MGH. N Engl J Med. 2007;356:1760-1769.
21. van Vlerken, L.E., Duan, Z., Seiden, M.V., Mansoor, M., Amiji, M.M. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multi-drug resistance in tumor cells. Cancer Res. 67:4843-4850, 2007.

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Research Interests

Our laboratory investigations focus on clinical studies to improve the response of tumors to drug therapies, and on animal studies to investigate methods to enhance drug delivery and decrease toxicity.

Selected Publications

1. O'Grady MA, Slater E, Sigurdson ER, Meropol NJ, Weinstein A, Lusch CJ, Sein E, Keeley P, Miller B, Engstrom PF, Cohen SJ. Assessing Compliance with National Comprehensive Cancer Network Guidelines for Elderly Patients with Stage III Colon Cancer: The Fox Chase Cancer Center Partners' Initiative. Clinical Colorectal Cancer. 2011 Jun;10(2):113-6.
2. Patel RR, Li T, Ross EA, Sesa L, Sigurdson ER, Bleicher RJ. The effect of simultaneous peripheral excision in breast conservation upon margin status. Ann Surg Oncol. 2010 Nov;17(11):2933-9.
3. Shaw CM, Zhu F, Lessin S, Sigurdson E. Effect of Body Mass Index on Overall Survival in Patients with Stage III Melanoma. Ann Surg Oncol. 2010 Feb;17:S111-S111.
4. Swoboda RK, Somasundaram R, Caputo L, Berencsi K, von Franzke P, Taylor DD, Marincola FM, Meropol NJ, Sigurdson E, Miller E, Herlyn D. Nucleophosmin is recognized by a cytotoxic T cell line derived from a rectal carcinoma patient. Int J Cancer. 2010 Sep;127(5):1124-30.
5. Stitzenberg KB, Sigurdson ER, Egleston BL, Starkey RB, Meropol NJ. Centralization of Cancer Surgery: Implications for Patient Access to Optimal Care. J Clin Oncol. 2009 Oct;27(28):4671-8.
6. Konski A, Li T, Sigurdson E, Cohen SJ, Small W, Spies S, Yu JQ, Wahl A, Stryker S, Meropol NJ. Use of molecular imaging to predict clinical outcome in patients with rectal cancer after preoperative chemotherapy and radiation. Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):55-9.
7. Turaka A, Freedman GM, Li T, Anderson PR, Swaby R, Nicolaou N, Goldstein L, Sigurdson ER, Bleicher RJ. Young age is not associated with increased local recurrence for DCIS treated by breast-conserving surgery and radiation. J Surg Oncol. 2009 Jul 1;100(1):25-31.
8. Bleicher RJ, Ciocca RM, Egleston BL, Sesa L, Evers K, Sigurdson ER, Morrow M. Association of routine pretreatment magnetic resonance imaging with time to surgery, mastectomy rate, and margin status. J Am Coll Surg. 2009 Aug;209(2):180-7; quiz 294-5.
9. Freedman GM, Anderson P, Litwin S, Swaby R, Nicolaou N, Sigurdson E, Ma C, Watkins-Bruner D, Morrow M, Goldstein L. Five-year Results of a Phase II Study of Hypofractionated IMRT with an Incorporated Boost for Breast Cancer. Int J Radiat Oncol Biol Phys. 2009;75(3):S77-S77.
10. Landry JC, Catalano P, Cohen SJ, Staley C, Sigurdson E, Feng Y, Benson AB. Phase II Study of Preoperative Radiation with Concurrent Capecitabine, Oxaliplatin and Bevacizumab followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients with Locally Advanced Rectal Cancer: ECOG 3204. Int J Radiat Oncol Biol Phys. 2009;75(3):S27-S28.
11. Konski A, Li TY, Sigurdson E, Cohen SJ, Small W, Spies S, Yu JQ, Wahl A, Stryker S, Meropol NJ. Use of molecular imaging to predict clinical outcome in patients with rectal cancer after preoperative chemotherapy and radiation. Int J Radiat Oncol Biol Phys 2009;74(1):55-9.
12. Abramowitz MC, Li T, Morrow M, Sigurdson ER, Anderson P, Nicolaou N, Freedman G. Dermal lymphatic invasion and inflammatory breast cancer are independent predictors of outcome after postmastectomy radiation. Am J Clin Oncol. 2009 Feb;32(1):30-3.

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GIST Research Laboratory

The primary goal of our work is the testing and evaluation of new therapies for sarcomas.  There are approximately 7,000 new cases of sarcomas diagnosed yearly with only 50% surviving their disease.  Current therapies do not lead to cures when sarcomas return.  Our group has focused on testing new therapies in advanced sarcomas.  Trials testing targeted therapies in the appropriate biologic context is sought.  Examples of such trials are the sarc-kinase inhibitor dasatanib and IGF-1R for sarcomas.  

We have a particular interest in novel therapies for Gastrotintestinal Stromal Tumors (GIST).  GIST are characterized by the presence of activating mutations, most commonly in KIT and PDGFRA.  We participated in the initial trials of imatinib and sunitinib.  We have been involved in testing many other kinase inhibitors as well as novel therapeutic agents such as heat shock protein inhibitors.  Our interest in GIST is supplemented by pre-clinical studies conducted in the GIST Research Laboratory.  Studies in the laboratory identified IGF-1R as a potential target in GIST lacking an activating mutation.  In vitro studies suggest activity of IGF-1R inhibition alone and in combination with KIT inhibition has anti-proliferative and pro-apoptotic effects.  We will be testing the benefit of IGF-1R inhibitors in GIST.

Selected Publications

1. Mitchell MA, Johnson JE, Pascarelli K, Beeharry N, Chiourea M, Gagos S, Lev D, von Mehren M, Kipling D, Broccoli D. Doxorubicin Resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres. Molecular Cancer Therapeutics, 9(3):682-92. Epub Mar 2, 2010.
2. Demetri GD, Casali PG, Blay JY, von Mehren M, Morgan JA, Bertulli R, Ray-Coquard I, Cassier P, Davey M, Borghaei H, Pink D, Debiec-Rychter M, Cheung W, Bailey SM, Veronese ML, Reichardt A, Fumagalli E, Reichardt P. A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Clinical Cancer Research 15(18):5910-6. Epub 2009 Sep 1.
3. Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of Neoadjuvant/Adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/Recurrent Operable Gastrointestinal Stromal Tumors (GIST) – early results of RTOG 0132. Journal of Surgical Oncology, 99(1):42-7, 2009.
4. Blay J-Y, von Mehren M, Samuels BL, Fanucchi MP, Ray-Coquard I, Buckley B, Gilles L, Lebedinsky C, Elsayed YA, Le Cesne A. Phase I Combination Study of Trabectedin and Doxorubicin in Patients With Soft Tissue Sarcoma. Clinical Cancer Research, 14:6656-6662, 2008
5. Tarn C, Rink L, Merkel E, Flieder D, Parhak H, Koumbi D, Testa J, Eisenberg B, von Mehren M, Godwin A. Insulin-like Growth Factor 1 Receptor is a Potential Therapeutic Target for Gastrointestinal Stromal Tumors. Proceedings of the National Academy of Sciences, 105(24):8387-92. Epub 2008 Jun 11, 2008.
6. von Mehren M, Schilder RJ, Cheng J, Temmer E, Cardoso T, Renshaw G, Bayever E, Zannikos P, Yuan Z, Cohen RB. A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies. Annals of Oncology, 19(10):1802-9, 2008.
7. Johnson J, Gettings EJ, Schwalm J, Pei J, Testa JR, Litwin S, von Mehren M, Broccoli D. Whole-Genome Profiling in Liposarcomas Reveals Genetic Alterations Common to Specific Telomere Maintenance Mechanisms. Cancer Research, 67: 9221-9228, 2007.
8. Tarn C, Skorobogatko YV, Taguchi T, Eisenberg B, von Mehren M, Godwin AK. Therapeutic Effect of Imatinib in Gastrointestinal Stromal Tumors: AKT Signaling Dependent and Independent Mechanisms. Cancer Research, 66(10):5477-86, 2006.
9. Johnson JE, Varkonyi RJ, Schwalm J, Cragle R, Klein-Szanto A, Patchefsky A, Cukierman E, von Mehren M, Broccoli D. Multiple Mechanisms of Telomere Maintenance exist in Liposarcomas. Clinical Cancer Research, 11(15):5347-55, 2005.
10. Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogayko YV, Heslin M, Eisenberg B, Birbe R, Patchefsky A, Dunbrack R, Arnoletti JB, von Mehren M, Godwin AK. Analysis of Kit mutations in Sporadic and Familial GIST: Therapeutic Implications using Protein Modeling. Clinical Cancer Research, 11(10):3668-77, 2005.
11. von Mehren M, Balcerzak SI, Kraft AS, Edmonson EK, Okuno SH, Davey M, McLaughlin S, Beard MT, and Rogatko A. Phase II trial of dolastatin-10, a novel anti-tubulin agent, in metastatic soft tissue sarcomas. Sarcoma, 8(4):107-112, 2004.
12. Frolov A, Chahwan S, Ochs M, Arnoletti, JP, Pan Z-Z, Favorova O, Fletcher J, von Mehren M, Eisenberg B, Godwin AK. Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors (GISTs). Molecular Cancer Therapeutics 2(8):699-709, 2003.
13. Demetri GD, von Mehren M, Blanke CD, Van Den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CDM, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New England Journal of Medicine 347(7):472-480, 2002.

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Structural Studies of Signaling Proteins Involved in Cell Migration and Cell Adhesion

My laboratory is interested in the structural and molecular basis for the signaling changes that allow tumors to spread by metastasis. Prevention of the spread of cancer cells from the primary tumor site is an important therapeutic approach for cancer treatment. Reduction of cell adhesion and enhancement of cell migration are key characteristics of cancer cells that are predisposed to metastasis. Recently, the MRL group of signaling adaptor proteins was found to be capable of regulating cell migration and adhesion by recruiting actin-binding proteins that mediate actin dynamics. Our research studies the recruitment of the MRL proteins to actin-binding proteins, and how this interaction regulates the cell adhesion and cell migration.  For this, we employ a combination of techniques, including X-ray crystallography, enzyme kinetics, mammalian cell culture, and genetic analysis. This research will contribute significantly to our understanding of the formation and regulation of cell adhesion and cell migration processes, and will facilitate the discovery of novel molecular targets for therapeutic intervention in cancer and other related diseases.

Selected Publications

1. Wynne JP*, Wu J*, Su W, Mor A, Patsoukis N, Boussiotis VA, Hubbard SR, Philips MR. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J Cell Biol. 2012 Oct 08. [Epub ahead of print]. *Equal contribution.
2. Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, Xu CF, Neubert TA, Skoda RC, Hubbard SR, Silvennoinen O. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol. 2011 Aug 14. [Epub ahead of print] PubMed
3. Depetris RS*, Wu J*, Hubbard, S.R. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nat Struct Mol Biol. 2009;16,833-9. *Equal contribution. PubMed
4. Wu J*, Li W*, Craddock BP, Foreman KW, Mulvihill MJ, Ji QS, Miller WT, Hubbard SR. Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor. EMBO J. 2008;27,1985-94. *Equal contribution. PubMed
5. Wu J, Tseng Y, Xu C, Neubert TA, White MF, and Hubbard SR. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol. 2008;15,251-8. PubMed
6. Bergamin E, Wu J, and Hubbard SR. Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3. Structure. 2006;14,1285-92. PubMed
7. Wu J, Bera AK, Kuhn RJ, and Smith JL. Structure of the flavivirus helicase: implications for catalytic activity, protein interactions, and proteolytic processing. J Virol. 2005;79,10268-77. PubMed

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Research Interests

Our current research includes:  1) Application of Immunohistochemistry (IHC) for both basic and clinical research, and 2) Gene regulation on embryogenesis, organogenesis, tumorigenesis and multi-drug resistance. The main focus is on the application of immunohistochemistry (IHC) and automatic quantitative analysis (AQUA) on both basic and clinical research, particularly in biomarker characterization and discovery.  Specifically, including:

1) Develop IHC assay for new biomarkers

2) Automated Quantitative Analysis (AQUA) assay development and validation

3) Ovarian cancer biology and multi-drug resistance

Previously, the Yang laboratory focused on understanding the molecular alterations of known and novel signaling pathways that regulate embryogenesis, organ morphogenesis, preneoplastic transformation and tumorigenicity.  Main projects involving: (1) Disabled-2 in mouse embryogenesis, epithelia positional organization and ovarian tumorigenesis.  (2) Basement membrane laminin and its receptors in tumor metastasis, kidney development & function, and neuromuscular development & function. The model systems used were: cell culture, tissue/organ culture, ES cell derived Embryoid Bodies (EBs), transgenic knock-out mouse and cre-loxP conditional knock-out mouse.

Selected Publications

1. Yang DH, McKee KK, Chen ZL, Mernaugh G, Strickland S, Zent R and Yurchenco PD. Renal collecting system growth and function depend upon embryonic gamma1 laminin expresseion. Development. 2011 Oct;138(20):4535-44. Epub 2011 Sep 8. PubMed
2. Yang D-H, Cai KQ, Roland IH, Smith ER and Xu XX Disabled-2 is an epithelial surface positioning gene. J Biol Chem. 2007 Apr 27;282(17):13114-22. PubMed
3. Yang D-H, Z Fazili, E.R. Smith, , Q Cai, A. Klein-Szanto, C. Cohen, IR Horowitz and X.X.Xu Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53 null background. Am. J. Path. 2006, 169:258-267. PubMed
4. Yang D-H, E.R. Smith, I.H. Roland, Z. Sheng, J.,He, W. D. Martin, J. D. Kambeth, T.H. Hamiton and X.X. Xu Disabled-2 is essential for endodermal cell positioning and structural formation during mouse embryogenesis. Dev. Biol.2002, 251:27-44. PubMed
5. Yang D-H, E.R. Smith, C. Cohen, C. Patriotis, A.K. Godwin, T.C. Hamilton and X.X.Xu Molecular events associated with dysplastic morphological transformation and initiation of ovarian tumorigenicity. Cancer 2002, 94: 2380-2392. PubMed

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Translational Proteomics

Yeung's research is concerned with the application of the basic research tools of biochemistry and biotechnology to medicine. The biochemistry studied includes nucleic acid chemistry, DNA damage lesions, and DNA repair nucleases enzymology; the biotechnology expertise includes automated DNA synthesis, enzymatic mutation detection, quantitative real-time PCR, mass spectrometry, and proteomics. These tools are applied to three main projects: a proteomic project seeking intervention targets in colon crypt cells that have sustained one-hit tumor suppressor mutations; the application of mass spectrometry for high sensitivity early detection of pancreatic cancer in pancreatic cyst fluids; and the search for the biomarkers of susceptibility and severity of chronic obstructive pulmonary disease (COPD). Yeung is also the director of the Biochemistry and Biotechnology Facility that includes chromatography, mass spectrometry, and proteomics

Selected Publications

1. Patel BB, Li XM, Dixon MP, Blagoi EL, Nicolas E, Seeholzer SH, Cheng D, He YA, Coudry RA, Howard SD, Riddle DM, Cooper HC, Boman BM, Conrad P, Crowell JA, Bellacosa A, Knudson A, Yeung AT, Kopelovich L. APC +/- alters colonic fibroblast proteome in FAP. Oncotarget. 2011 Mar;2(3):209-8. PubMed
2. Bellacosa A, Godwin AK, Peri S, Devarajan K, Caretti E, Vanderveer L, Bove B, Slater C, Zhou Y, Daly M, Howard S, Campbell K, Nicolas E, Yeung AT, Clapper ML, Crowell JA, Lynch HT, Ross E, Kopelovich L, Knudson AG. Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations. Cancer Prev. Res., 3:48-61, 2010. PubMed
3. Ke E, Patel BB, Liu T, Li XM, Haluszka O, Hoffman J, Ehya H, Young NA, Watson JC, Weinberg D, Nguyen M, Cohen SJ, Meropol NJ, Litwin S, Tokar JL, Yeung AT. Proteomic analyses of pancreatic cyst fluids. Pancreas. 2009;38:e33-42. PubMed
4. Yeung AT, Patel BB, Li XM, Seeholzer SH, Coudry RA, Cooper HS, Bellacosa A, Boman BM, Zhang T, Litwin S, Ross EA, Conrad P, Crowell JA, Kopelovich L, Knudson A. One-hit effects in cancer: Altered proteome of morphologically normal colon crypts in familial adenomatous polyposis. Cancer Res. 2008;68:7579-86. PubMed
5. Patel BB, He AY, Li X-M, Frolov A, Vanderveer L, Slater C, Schilder R, Von Mehren M, Godwin AK, Yeung AT. Molecular mechanisms of action of Imatinib Mesylate in human ovarian cancer: a proteomic analysis. Cancer Genomics Proteomics. 2008;5:137-149. Accepted prior to April 7, 2008. PubMed

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Research Interests

Cancer is due to cells that run out of control. My laboratory aims to study the body’s immune response to cancer. Understanding why the response to cancer weakens the body will allow us to strengthen the ability to control the disease.

Interests:

-Contribute to the development of animal models for lymphoma. 
-Investigation and description of new or unusual hemopoietic malignancies.

Selected Publications

1. Reyes VE Jr, Al-Saleem T, Robu VG, Smith MR. Extranodal NK/T-cell lymphoma nasal type: Efficacy of pegaspargase. Report of two patients from United States and review of literature. Leuk Res. 2010 Jan;34(1):e50-4. Epub 2009 Sep 27. PubMed
2. Pollack A, Bae K, Khor LY, Al-Saleem T, Hammond ME, Venkatesan V, Byhardt RW, Asbell SO, Shipley WU, Sandler HM. The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group trial 92002. Clin Cancer Res. 2009 Sep 1;15(17):5478-84. Epub 2009 Aug 25. PubMed
3. Kadariya Y, Yin B, Tang B, Shinton SA, Quinlivan EP, Hua X, Klein-Szanto A, Al-Saleem TI, Bassing CH, Hardy RR, Kruger WD. Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma. Cancer Res. 2009 Jul 15;69(14):5961-9. Epub 2009 Jun 30. PubMed
4. Khor LY, Bae K, Paulus R, Al-Saleem T, Hammond ME, Grignon DJ, Che M, Venkatesan V, Byhardt RW, Rotman M, Hanks GE, Sandler HM, Pollack A. MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer; RTOG 92-02. J Clin Oncol. 2009 Jul 1;27(19):3177-84. Epub 2009 May 26. PubMed
5. Gitelson E, Al-Saleem T, Smith MR. Lymphomatoid granulomatosis; challenges in diagnosis and treatment. Clin Adv Hematol Oncol. 2009 Jan;7(1):68-70. PubMed
6. Shafer D, Wu H, Al-Saleem T, Reddy K, Borghaei H, Lessin S, Smith M. Cutaneous precursor B-Cell lymphoblastic lymphoma in2 adult patients: clinicopathologic and molecular cytogenetic studies with a review of the literature. Arch Dermatol. 2008 Sep;144(9):1155-62. PubMed
7. Jambusaria A, Shafer D, Wu H, Al-Saleem T, Perlis C. Cutaneous plasmablastic lymphoma. J Am Acad Dermatol. 2008 Apr;58(4):676-8. PubMed
8. Rothman J, Crispen PL, Wong YN, Al-Saleem T, Fox E, Uzzo RG. Pathologic concordance of sporadic synchronous bilateral renal masses. Urology. 2008 Jul;72(1):138-42. Epub 2008 Mar 12. PubMed
9. Potapova A, Hoffman AM, Godwin AK, Al-Saleem T, Cairns P. Promoter hypermethylation of the PALB2 susceptibility gene in inherited and sporadic breast and ovarian cancer. Cancer Res. 2008 Feb 15;68(4):998-1002. PubMed
10. D'Ambrosio DJ, Hanlon AL, Al-Saleem T, Feigenberg SJ, Horwitz EM, Uzzo RG, Pollack A, Buyyounouski MK. The proportion of prostate biopsy tissue with Gleason pattern 4 or 5 predicts for biochemical and clinical outcome after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1082-7. Epub 2007 Jan 22. PubMed
11. Narra K, Borghaei H, Al-Saleem T, Höglund M, Smith MR. Pure red cell aplasia in B-cell lymphoproliferative disorder treated with rituximab: report of two cases and review of the literature. Leuk Res. 2006 Jan;30(1):109-14. Epub 2005 Jul 25. PubMed
12. Gitelson E, Al-Saleem T, Millenson M, Lessin S, Smith MR. Cutaneous B-cell lymphoma responds to rituximab: a report of five cases and a review of the literature. Leuk Lymphoma. 2006 Sep;47(9):1902-7. PubMed
13. Al-Saleem T, Balsara BR, Liu Z, Feder M, Testa JR, Wu H, Greenberg RE. Renal oncocytoma with loss of chromosomes Y and 1 evolving to papillary carcinoma in connection with gain of chromosome 7. Coincidence or progression? Cancer Genet Cytogenet. 2005 Nov;163(1):81-5. PubMed
14. Al-Saleem T, Al-Mondhiry H. Immunoproliferative small intestinal disease (PSID): a model for mature B-cell neoplasms. Blood. 2005 Mar 15;105(6):2274-80. Epub 2004 Nov 12. PubMed
15. Dulaimi E, Ibanez de Caceres I, Uzzo RG, Al-Saleem T, Greenberg RE, Polascik TJ, Babb JS, Grizzle WE, Cairns P. Promoter hypermethylation profile of kidney cancer. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3972-9. PubMed

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Cytokine Signaling in Host Innate Immune and Anti-Tumor Responses

A key component of mammalian immunity against viruses and cancer is a family of cytokines called the interferons (IFNs, so called because they ‘interfere’ with virus replication). The IFNs are classified into two groups, type I and type II. Type I (α/β) IFNs are produced by most cell types in response to viral infection, whereas type II IFN (called IFN-γ) is made by a select subset of immune system cells and is not virus inducible.

Type I IFNs (e.g.IFN-α2) were approved by the Food & Drug Administration (FDA) in 1986 as the first commercial anticancer biotherapeutic, and are currently employed in the treatment of over twenty human cancers. It is thought that the IFNs exert their antitumor effects by modulation and reactivation of the immune response to the tumor and/or by direct tumoricidal activity, but the underlying mechanisms remain poorly described. In the years preceding their approval by the FDA, the IFNs were touted as a potential ‘silver bullet’ cure for many forms of cancer, even making the cover of Time magazine in 1980. Unfortunately, these cytokines have, in recent years, fallen out of favor with many oncologists because of their very unpleasant side-effects. Nevertheless, IFNs continue to be used in the clinic and provide spectacular cures of several highly malignant cancers (such as AIDS-associated lymphomas and metastatic renal cell carcinoma), highlighting their Janus-faced nature.

The primary problem with IFN therapy is that IFN is, of course, also a potent antiviral cytokine and triggers a powerful innate immune response in the patient, whose body responds to systemic therapeutic IFN as it would to an acute viremia. Efforts are currently underway to target IFN delivery to the tumor site (particularly for solid tumors), but an equally compelling avenue of research is to determine the mechanism(s) by which IFNs selectively mediate their cytotoxic effects, and exploit these mechanisms to make IFN a more potent therapeutic (and thereby reduce its effective dose by, hopefully, at least one order of magnitude). Our laboratory is therefore very interested in the molecular processes by which IFNs specifically exert their anti-proliferative effects. We have recently identified novel pathways by which the IFNs induce cell survival and death and are currently elucidating these mechanisms.

Another area of research in the laboratory is to understand how type I IFNs and other antiviral genes are induced after virus infection. In a current model, virus replication in the cytosol activates at least three classes of transcription factors to induce primary antiviral genes (including type I IFNs). Of these factors, we are particularly interested in NF-κB, and are currently defining its mechanism of activation and role in antiviral responses.

Selected Publications

1. Balachandran S, Beg AA. Defining roles for NF-κB in antivirus responses: revisiting the interferon-β enhanceosome paradigm. PLoS Pathog. 2011;7:e1002165. PubMed
2. Irrinki KM, Mallilankaraman K, Thapa RJ, Chandramoorthy HC, Smith FJ, Jog NR, Gandhirajan RK, Kelsen SG, Houser SR, May MJ, Balachandran S, Madesh M. Requirement of FADD, NEMO and BAX/BAK for aberrant mitochondrial function in TNFα-induced necrosis. Mol Cell Biol. 2011;31:3745-58. PubMed
3. Thapa RJ, Basagoudanavar S, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S. NF-κB protects cells from interferon-γ-induced RIP1-dependent necroptosis. Mol Cell Biol. 2011;31:2934-46. PubMed
4. Basagoudanavar SH, Thapa RJ, Nogusa S, Wang J, Beg AA, Balachandran S. Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses. J Virol. 2011;85:2599-610. PubMed
5. Wang J, Basagoudanavar SH, Wang X, Hopewell E, Albrecht R, Garcia-Sastre A, Balachandran S, Beg AA. NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication. J Immunol. 2010;185:1720-29. PubMed
6. Balachandran S, Thomas E, Barber GN. A FADD-dependent innate immune mechanism in mammalian cells. Nature. 2004;432:401-5. PubMed
7. Balachandran S, Barber GN. Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell. 2004;5:51-65. PubMed
8. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity. 2000;13:129-41. PubMed
9. Balachandran S, Kim CN, Yeh WC, Mak TW, Bhalla K, Barber GN. Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J. 1998;17:6888-902. PubMed

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Signal Transduction in Natural Killer Cells

Natural killer (NK) cells constitute about 10-15% of the normal lymphocytes in human peripheral blood. They are important sentinels of the innate immune system that can detect and kill tumor cells and virus-infected cells, and produce cytokines, including interferon-γ and tumor necrosis factor-α. NK cells are regulated by a dynamic balance between positive and negative intracellular signals that are transduced from cell surface activating and inhibitory receptors. This makes them an ideal cellular model system to study signal transduction crosstalk. Our goal is to understand the molecular mechanisms by which NK cells recognize and attack abnormal cells in the body, but are tolerant toward normal cells. This knowledge should lead to therapeutic strategies that can enhance NK cell responsiveness toward tumors and viruses in patients.

Killer cell immunoglobulin-like receptors (KIRs) are key regulators of human NK cell function. KIRs bind major histocompatibility complex class I (MHC-I) molecules on the surfaces of all healthy normal cells in the body. Upon detecting MHC-I, KIRs transduce a negative intracellular signal that suppresses NK cell killing responses. The inhibitory signal derived when KIR detect MHC-I is important for establishing tolerance toward normal cells. Many abnormal tumor cells and virally infected cells eliminate MHC-I expression, however, which abolishes the KIR negative signals and releases the NK cells to specifically attack only these abnormal cells and eliminate them from the body. We are studying the molecular mechanisms controlling the surface expression of KIRs. Improved understanding of the regulation of KIR surface expression should lead to therapeutic treatments to alter their surface expression and thereby change the NK cell activation threshold to more efficiently attack tumor cells and virus-infected cells.

Alternatively, KIR2DL4 is an activating receptor that stimulates NK cells to secrete cytokines, but uniquely does not stimulate tumor cell killing. Interestingly, KIR2DL4 is only expressed on a small subset of NK cells. Furthermore, receptor expression is upregulated in stimulated NK cells, and some individuals cannot express this receptor at all, due to a common genetic polymorphism. The physiological implications and potential for disease susceptibility resulting from the inability to express KIR2DL4 in some individuals are currently unknown and warrant further detailed study. Our overall goals are to define the molecular mechanisms controlling the unique expression and function of KIR2DL4. The results will allow us to better understand its role in regulating inflammation and fighting cancer.

Selected Publications

1. MacFarlane IV AW, Yamazaki T, Fang M, Sigal LJ, Kurosaki T, Campbell KS. Enhanced NK cell development and function in BCAP-deficient mice. Blood. 2008;112:131-140. PubMed
2. Binyamin L, Alpaugh RK, Hughes TL, Lutz CT, Campbell KS, Weiner LM. Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J Immunol. 2008;180:6392-6401. PubMed
3. Purdy, A.K. and Campbell, K.S. SHP-2 expression negatively regulates NK cell function. J. Immunol. 2009;183:7234-7243 PubMed
4. Campbell, K. S., Editor. Natural Killer Cell Protocols: Cellular and Molecular Methods, Second Edition, Methods in Molecular Biology Series, Vol. 612, Humana Press/Springer Science, New York, NY, 2010.
5. Miah, S.M.S., Purdy, A.K., Rodin, N.B., MacFarlane IV, A.W., Oshinsky, J., Alvarez-Arias, D.A., and Campbell, K.S. Ubiquitylation of an internalized killer cell Ig-like receptor by Triad3A disrupts sustained NF-κB signaling. J. Immunol., In press.

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1. Developmental therapeutics for multiple myeloma and amyloidosis

Multiple myeloma is a cancer of the bone marrow affecting 20,000 new U.S. patients each year, in which proliferation of malignant bone marrow plasma cells leads to bone lesions, kidney damage, anemia, and recurrent infections.  Systemic light-chain (AL) amyloidosis is a rare, related plasma cell disorder in which a toxic misfolded protein is deposited into organs such as heart, kidney, and liver, leading to eventual organ dysfunction and failure. Novel drugs such as thalidomide, lenalidomide, and bortezomib, as well as advances in hematopoietic stem cell transplantation, have significantly improved outcomes for myeloma and amyloidosis patients in the past decade, but both diseases remain largely incurable, and new approaches to treatment continue to be needed.

Fortunately, scientific advances in the underlying pathophysiology of these diseases have led to a number of new targets for therapeutic development.  Our program is dedicated to the evaluation of promising new agents in early-stage clinical trials, both for newly-diagnosed and relapsed/refractory patients.  Such trials advance our understanding of how best to treat these difficult diseases, and importantly offer patients access to agents that may not yet be available, often providing additional options when standard therapeutic approaches have been exhausted.  Our current protocols are studying molecularly-targeted inhibitors of kinesin spindle protein and NEDD8-activating enzyme, which are involved in myeloma cell cycle progression and protein degradation pathways, respectively, as well as monoclonal antibodies against BAFF or IL-6, two signaling molecules which promote myeloma cell proliferation and survival.  Planned studies for 2011 include evaluation of new proteasome inhibitors for myeloma and amyloidosis, as well as trials involving novel immunomodulatory drugs, monoclonal antibodies, and vaccines.  We also continue to collaborate with the Temple/Fox Chase Bone Marrow Transplant program to explore ways to improve autologous stem cell transplantation as a treatment modality for these diseases.

2. Modulation of anti-tumor immunity in lymphoid malignancies

A growing body of literature has demonstrated that the clinical behavior of certain cancers, including lymphoid malignancies like multiple myeloma and lymphoma, is determined not only by the intrinsic biology of the malignant cells, but also by the ability of the host immune system to recognize and respond to these cells. Our pre-clinical/translational research program is dedicated to gaining greater understanding of immune cell function in lymphoid malignancy patients, as well as exploring therapeutic approaches to augment immune responses against these diseases. In collaboration with Kerry Campbell, Ph.D., we are using multi-parameter flow cytometry and ex vivo functional assays to extensively characterize immune cell phenotype and function in lymphoid malignancy patients, with a particular focus on natural killer (NK) cell activity and how these cells are affected by currently-used therapies. From a therapeutic perspective, we are interested in a novel class of antibodies that enhance T or NK cell-mediated anti-tumor immunity via modulation of signaling through receptors expressed on their surface, such as GITR (glucocorticoid-induced TNF receptor), CD137/4-1BB, or the KIR (killer-cell immunoglobulin-like receptor) family. We also are exploring therapeutic vaccine approaches to stimulate anti-tumor immunity, with a pilot clinical trial using a recombinant MAGE-A3 protein vaccine currently in development for multiple myeloma patients.

Selected Publications

1. Landau H, Pandit-Taskar N, Hassoun H, Cohen A, Lesokhin A, Lendvai N, Drullinsky P, Schulman P, Jhanwar S, Hoover E, Bello C, Riedel E, Nimer S, Comenzo RL. Sequential administration of bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) is effective treatment for patients with untreated high-risk or primary resistant multiple myeloma (MM). Submitted for publication.
2. Shah, JJ, Cohen AD, Zonder JA, Kaufman JL, Burt SM, Freeman BB, Rush S, Ptaszynski AM, Orlowski RZ, Lonial S. Phase I trial of ARRY-520 in relapsed/refractory multiple myeloma (RR MM). J Clin Oncol. 2010;28:15s. (suppl; abstr 8132).
3. Cohen AD*, Schaer DA*, Liu C, Li Y, Hirschhorn-Cymerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, Merghoub T, Houghton AN, Wolchok JD. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. Plos ONE. 2010;5:e10436.
4. Cohen AD, Lu P, Gnjatic S, Hoffman J, Ritter E, Zhou P, Teruya-Feldstein J, Wang L, Jungbluth A, Koehne G, Hassoun H, Jhanwar S, Nimer S, Comenzo RL. Prognostic significance of cancer-testis antigen expression and immunity in newly-diagnosed multiple myeloma. Lymphoma and Myeloma 2009: An International Congress on Hematologic Malignancies, New York, NY. Abstract #O-00003.
5. Anderson KC, Alsina M, Bensinger W, Biermann JS, Chanan-Khan A, Cohen AD, Devine S, Djulbegovic B, Gasparetto C, Huff CA, Jagasia M, Medeiros BC, Meredith R, Raje N, Schriber J, Singhal S, Somlo G, Stockerl-Goldstein K, Tricot G, Vose JM, Weber D, Yahalom J, Yunus F. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Journal of the National Comprehensive Cancer Network. 2009;7:908-42.
6. Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T, Cohen AD, Avogadri F, Lesokhin AM, Weinberg AD, Wolchok JD, Houghton AN. OX40 engagement and chemotherapy combination provides potent anti- tumor immunity with concomitant regulatory T cell apoptosis. Journal of Experimental Medicine. 2009;206:1103-16.
7. Duan F, Lin Y, Liu C, Engelhorn ME, Cohen AD, Curran M, Sakaguchi S, Merghoub T, Terzulli S, Houghton AN, Wolchok JD. Immune rejection of mouse tumors expressing mutated self. Cancer Research. 2009;69:3545-53.
8. Lebovic D, Hoffman J, Levine BM, Hassoun H, Landau H, Goldsmith Y, Maurer MS, Steingart RM, Cohen AD, Comenzo RL. Predictors of survival in patients with systemic light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone. British Journal of Haematology. 2008;143:369-73.
9. Hassoun H, Flombaum C, D’Agait VD, Rafferty BT, Cohen A, Klimek VM, Boruchov A, Kewalramani T, Reich L, Nimer SD, Comenzo RL. High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease. Bone Marrow Transplantation. 2008;42:405-12.
10. Comenzo RL, Steingart RM, Cohen AD. Comment on “High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.” New England Journal of Medicine. 2008;358:92.
11. Cohen AD, Zhou P, Chou J, Teruya-Feldstein J, Reich L, Hassoun H, Levine B, Filippa D, Riedel E, Kewalramani T, Stubblefield M, Fleisher M, Nimer S, Comenzo RL. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain (AL-) amyloidosis: results of a phase II trial. British Journal of Haematology. 2007;139:224-33.
12. Perales M-A, Diab A, Cohen AD, Huggins DW, Guevara-Patino JA, Hubbard VM, Engelhorn ME, Kochman AA, Eng JM, Mortazavi F, Alpdogan O, Terwey TH, Heller G, Wolchok JD, Houghton AN, van den Brink MRM. DNA immunization against tissue-restricted antigens enhances tumor immunity after allogeneic hematopoietic stem cell transplantation. Journal of Immunologo. 2006;177:4159-67.
13. Cohen AD, Diab A, Perales M-A, Wolchok JD, Rizzuto G, Merghoub T, Huggins D, Liu C, Turk MJ, Restifo NP, Sakaguchi S, Houghton AN. Agonist anti–GITR antibody enhances vaccine-induced CD8+ T-cell responses and tumor immunity. Cancer Research. 2006;66: 4904-12.
14. Guevara-Patino JA, Engelhorn ME, Turk MJ, Liu C, Duan F, Rizzuto G, Cohen AD, Merghoub T, Wolchok JD, Houghton AN. Optimization of a self-antigen for presentation of multiple epitopes in cancer immunity. Journal of Clinical Investigation. 2006;116:1382-90.
15. Hassoun H, Reich L, Klimek VM, Dhodapkar M, Cohen A, Kewalramani T, Zimman R, Drake L, Riedel ER, Hedvat CV, Teruya-Feldstein J, Filippa DA, Fleisher M, Nimer SD, Comenzo RL. Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma. British Journal of Haematology. 2006;132:155-61.
16. Cohen AD, Zhou P, Xiao Q, Fleisher M, Kalakonda N, Akhurst T, Moscowitz C, Dhodapkar MV, Teruya-Feldstein J, Filippa D, Comenzo RL. Systemic AL amyloidosis due to non-Hodgkin’s lymphoma: an unusual clinicopathologic association. British Journal of Haematology. 2004;124: 309-14.

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Fetal and Adult B Lymphocyte Differentiation

B lymphocyte development in mouse, as in humans, takes place in the fetal liver before birth and shifts shortly thereafter to the bone marrow, where it continues throughout life. The generation of B cells is a highly ordered process, orchestrated by a number of transcription factors that regulate expression of a set of lymphoid and B lineage specific genes at well-defined developmental stages. During this process, immunoglobulin (Ig) heavy chain D-to-J rearrangements in pro-B cells precede V-to-DJ rearrangements that eventually yield functional heavy chain protein in pre-B cells. In pre-B cells, this Ig heavy chain protein associates with B lineage specific surrogate light chain components to form a pre-BCR. This signals events required for development to later stages where Ig light chain rearrangement takes place and is expressed. This then becomes associated with heavy chain, allowing a complete Ig molecule, the BCR, to be expressed on the surface of a newly formed B cell. The interests of my laboratory focus on three areas related to this process: 1) elucidating the stage(s) and molecular/cellular interactions taking place as B cell precursors become progressively restricted to the B lineage; 2) determining the role of Ig heavy chain VDJ structures in guiding B cell development; and 3) comparing fetal and adult B cell development, particularly as related to the preferential generation of autoreactive malignant-prone CD5+ ("B-1") B cells during embryogenesis. We are also investigating the peripheral maturation of B cells in spleen and recently, starting a project to mark B cells in the zebrafish.

Selected Publications

1. Amin RH, Cado D, Nolla H, Huang D, Shinton SA, Zhou Y, Hardy RR, Schlissel MS. Biallelic, ubiquitous transcription from the distal germline Ig kappa locus promoter during B cell development. Proc Natl Acad Sci U S A. 2009 Jan;106(2):522-7. PubMed
2. Hardy RR. B lymphocyte development and biology. In: Paul WE, editor. Fundamental immunology. Philadelphia: Wolters Kluwer / Lippincott Williams & Wilkins; 2008. p. 237-69.
3. Hardy RR, Kincade PW, Dorshkind K. The protean nature of cells in the B lymphocyte lineage. Immunity. 2007 Jun;26(6):703-14. PubMed
4. Kitaura Y, Jang IK, Wang Y, Han YC, Inazu T, Cadera EJ, Schlissel M, Hardy RR, Gu H. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases cbl and Cbl-b. Immunity. 2007 May;26(5):567-78. PubMed
5. Hardy RR. B-1 B cells: development, selection, natural autoantibody and leukemia. Cur Opin Immunol. 2006;18:547-55. PubMed
6. Rumfelt LL, Zhou Y, Rowley BM, Shinton SA, Hardy RR. Lineage specification and plasticity in CD19(-) early B cell precursors. J Exp Med. 2006 Mar;203(3):675-87. PubMed
7. Wen L, Brill-Dashoff J, Shinton SA, Asano M, Hardy RR, Hayakawa K. Evidence of marginal-zone B cell-positive selection in spleen.[see comment]. Immunity. 2005 Sep;23(3):297-308. PubMed
8. Maier H, Ostraat R, Gao H, Fields S, Shinton SA, Medina KL, Ikawa T, Murre C, Singh H, Hardy RR, Hagman J. Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Nat Immunol. 2004 Oct;5(10):1069-77. PubMed
9. Hayakawa K, Asano M, Shinton SA, Gui M, Wen LJ, Dashoff J, Hardy RR. Positive selection of anti-Thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J Exp Med. 2003 Jan;197(1):87-99. PubMed

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Natural Autoreactive B cell Development and Cancer

B lymphocyte development progresses through several critical stages, initially establishing the antigen receptor repertoire and thereafter subject to selection influenced by the self-microenvironment. Strong self-reactivity results in deletion or inactivation of these cells during development, a process termed "negative selection" or "tolerance." However, not all autoreactive B cells are treated in this way. Rather, B cells with receptors specific for certain self-antigens persist for a long time without provoking autoimmune disease. Our research explores such natural autoreactive lymphocytes: the mechanisms whereby they develop, their functional significance, and their potential for dysregulation in relation to autoimmune disease and lymphoma development.

Natural autoreactive B cells bear unmutated B Cell antigen Receptors (BCRs) specific for certain self-antigens and such cells are found in healthy animals. A significant fraction of natural autoreactive IgM⁺ B cells are established early in ontogeny, as fetal B cells or "B-1", and are maintained as a self-renewing B cell population, capable of secreting autoantibody into serum. We have proposed that these natural autoreactive B cells and the autoantibody they produce constitute a part of the innate immune system, playing roles that complement and cooperate with adaptive immunity. Importantly, a characteristic feature of autoreactive B-1 cells is their expression of CD5. This CD5⁺ IgM⁺ phenotype resembles chronic B cell leukemia/lymphoma cells (B CLL) as well as B cells found in certain autoimmune diseases in mice and humans. This prompts us to consider that such long-maintained CD5⁺ B-1 cells, generated by self-antigen signaling, may constitute a pool of cells with a higher potential for malignant transformation. Our focus has been on understanding the mechanism of B cell development, in order to provide a comprehensive view on B subsets, and their potential for dysregulated growth.

Selected Publications

1. Wen L, Brill-Dashoff J, Shinton SA et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity. 2005;23(3):297-308. PubMed
2. Hayakawa K, Asano M, Shinton SA et al. Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J Exp Med. 2003;197(1):87-99. PubMed
3. Hardy RR, Hayakawa K. B cell development pathways. Annu Rev Immunol. 2001;19:595-621. PubMed
4. Hayakawa K, Asano M, Shinton SA et al. Positive selection of natural autoreactive B cells. Science. 1999;285(5424):113-6. PubMed
5. Hayakawa K, Hardy RR. Normal, autoimmune, and malignant CD5+ B cells: the Ly-1 B lineage? Annu Rev Immunol. 1988;6:197-218. PubMed

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T Lymphocyte Development and Signal Transduction

Our laboratory focuses on fundamental issues in T lymphocyte development and signal transduction. To this end we have developed mouse models with specific defects of the T lymphoid lineage: 1) an induced mutant lacking the CD3δ component of the TCR signalling complex, which is blocked in positive selection of a? T lineage cells, and 2) a spontaneous mutant line carrying an autosomal recessive mutation which blocks the generation of CD4+ but not CD8+ T cells, refered to as "helper-deficient" or HD-/- mice.

The TCR is responsible for antigen-specific recognition and differential signal transduction leading to alternate cellular responses in both immature and mature T cells. For immature thymocytes alternate signals lead to either death by apoptosis (negative selection) or activation and further differentiation (positive selection). Important issues that we have examined are whether alternate responses are achieved through quantitative and/or qualitative differences in TCR-mediated signalling and whether individual components of the TCR signalling complex possess unique or redundant functions. Our work in this area has focused on the in vivo manipulation of the structure and expression of the TCR complex using unique knockout and transgenic mouse models.

T cell maturation involves key branch points at which cells choose between commitment to different lineages, i.e. β versus α T cell lineages and CD4+ helper versus CD8+ killer lineages. Commitment to the helper or killer lineages correlates precisely with the specificity (restriction) of a thymocyte's TCR towards either class I or II MHC. Although this process has been intensively studied at the phenomenological level, the intracellular pathways controlling it remain obscure. Our work in this area has focussed on the characterization of a unique line of spontaneous mutant mice, HD-/- mice, which are blocked in the generation of CD4+ helper T cells. These mice carry a specific defect in a pathway controlling lineage commitment and represent an important new tool in achieving a mechanistic understanding of this process. We are interested in the further functional characterization and genetic mapping of this interesting mutation.

Selected Publications

1. Jones-Mason, ME, Zhao, X, Kappes, D, Lasorella, A, Iavarone, A, Zhuang, Y. E protein transcription factors are required for the development of CD4(+) lineage T cells. Immunity 2012; 36:348-61. PubMed
2. Aliahmad, P, Kadavallore, A, de la Torre, B, Kappes, D, Kaye, J. TOX is required for development of the CD4 T cell lineage gene program. J Immunol 2011; 187:593159-40. PubMed
3. Kappes DJ. Developing intestinal fortitude. Nat Immunol. 2011; 12(4):281-2. PubMed
4. Kappes, DJ. Expanding roles for ThPOK in thymic development. Immunol Rev 2010; 238:182-94. PubMed
5. De Keersmaecker K, Real PJ, Della Gatta G, Palomero T, Sulis ML, Tosello V, Van Vlierberghe P, Barnes K, Castillo M, Sole X, Hadler M, Lenz J, Aplan PD, Kelliher M, Kee BL, Pandolfi PP, Kappes D, Gounari F, Petrie H, Van der Meulen J, Speleman F, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Soulier J, Avran D, Cave H, Dastugue N, Raimondi S, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med. 2010; 16(11):1321-7. PubMed
6. Kim, ST, Touma, M, Takeuchi, K, Sun, ZY, Dave, VP, Kappes, DJ, Wagner, G, Reinherz, EL. Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors. J Immunol 2010; 185:2951-9. PubMed
7. Lee, SY, Stadanlick, J, Kappes, DJ, Wiest, DL. Towards a molecular understanding of the differential signals regulating alphabeta/gammadelta T lineage choice. Semin Immunol 2010; 22:237-46. PubMed
8. Engel, I, Hammond, K, Sullivan, BA, He, X, Taniuchi, I, Kappes, D, Kronenberg, M. Co-receptor choice by V alpha14i NKT cells is driven by Th-POK expression rather than avoidance of CD8-mediated negative selection. J Exp Med 2010; 207:1015-29. PubMed
9. He X, Park K, Kappes DJ. The role of ThPOK in control of CD4/CD8 lineage commitment. Annu Rev Immunol. 2010; 28:295-320. PubMed
10. Lauritsen JP, Wong GW, Lee SY, Lefebvre JM, Ciofani M, Rhodes M, Kappes DJ, Zuniga-Pflucker JC, Wiest DL. Marked induction of the helix-loop-helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent. Immunity. 2009; 31(4):565-75. PubMed
11. He X, Park K, Wang H, Zhang Y, Hua X, Li Y, Kappes DJ. CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity. 2008; 28(3):346-58. PubMed
12. Kappes D, Hagman J. Lymphocyte development - Regulation of B and T lymphoid cell development. Curr Opin Immunol. 2007; 19(2):113-5.
13. Kappes DJ. CD4 and CD8: Hogging all the Lck. Immunity. 2007; 27(5):691-3. PubMed
14. Haks, MC, Lefebvre, JM, Lauritsen, JP, Carleton, M, Rhodes, M, Miyazaki, T, Kappes, DJ, Wiest, DL. Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage. Immunity 2005; 22:595-606. PubMed
15. He, X, Dave, VP, Zhang, Y, Hua, X, Nicolas, E, Xu, W, Roe, BA, Kappes, DJ. The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 2005; 433:826-33. PubMed
16. Hayes, SM, Laky, K, El-Khoury, D, Kappes, DJ, Fowlkes, BJ, Love, PE. Activation-induced modification in the CD3 complex of the gammadelta T cell receptor. J Exp Med 2002; 196:1355-61. PubMed
17. Malstrom, S, Tili, E, Kappes, D, Ceci, JD, Tsichlis, PN. Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus. Proc Natl Acad Sci USA 2001; 98:14967-72. PubMed
18. Delgado, P, Fernandez, E, Dave, V, Kappes, D, Alarcon, B. CD3delta couples T-cell receptor signalling to ERK activation and thymocyte positive selection. Nature 2000; 406:426-30. PubMed
19. Kappes, DJ, Lawrence, DM, Vaughn, MM, Davė, VP, Belman, AR, Rall, GF. Protection of CD3 delta knockout mice from lymphocytic choriomeningitis virus-induced immunopathology: implications for viral neuroinvasion. Virology 2000; 269:248-56. PubMed
20. Gui, M, Wiest, DL, Li, J, Kappes, D, Hardy, RR, Hayakawa, K. Peripheral CD4 T cell maturation recognized by increased expression of Thy-1/CD90 bearing the 6C10 carbohydrate epitope. J Immunol 1999; 163:4796-804. PubMed
21. Keefe, R, Dave, V, Allman, D, Wiest, D, Kappes, DJ. Regulation of lineage commitment distinct from positive selection. Science 1999; 286:1149-53. PubMed
22. Dave, VP, Allman, D, Wiest, DL, Kappes, DJ. Limiting TCR expression leads to quantitative but not qualitative changes in thymic selection. J Immunol 1999; 162:5764-74. PubMed
23. Dave, VP, Keefe, R, Berger, MA, Drbal, K, Punt, JA, Wiest, DL, Alarcon, B, Kappes, DJ. Altered functional responsiveness of thymocyte subsets from CD3delta-deficient mice to TCR-CD3 engagement. Int Immunol 1998; 10:1481-90. PubMed
24. Dave, VP, Allman, D, Keefe, R, Hardy, RR, Kappes, DJ. HD mice: a novel mouse mutant with a specific defect in the generation of CD4( ) T cells. Proc Natl Acad Sci USA 1998; 95:8187-92. PubMed
25. Berger, MA, Dave, V, Rhodes, MR, Bosma, GC, Bosma, MJ, Kappes, DJ, Wiest, DL. Subunit composition of pre-T cell receptor complexes expressed by primary thymocytes: CD3 delta is physically associated but not functionally required. J Exp Med 1997; 186:1461-7. PubMed
26. Dave, VP, Cao, Z, Browne, C, Alarcon, B, Fernandez-Miguel, G, Lafaille, J, de la Hera, A, Tonegawa, S, Kappes, DJ. CD3 delta deficiency arrests development of the alpha beta but not the gamma delta T cell lineage. EMBO J 1997; 16:1360-70. PubMed
27. Kappes, DJ, Alarcon, B, Regueiro, JR. T lymphocyte receptor deficiencies. Curr Opin Immunol 1995; 7:441-7. PubMed
28. Monos, DS, Czanky, E, Ono, SJ, Radka, SF, Kappes, D, Strominger, JL. L cells expressing DQ molecules of the DR3 and DR4 haplotypes: reactivity patterns with mAbs. Immunogenetics 1995; 42:172-80. PubMed
29. Kappes, DJ, Browne, CP, Tonegawa, S. Identification of a T-cell-specific enhancer at the locus encoding T-cell antigen receptor gamma chain. Proc Natl Acad Sci USA 1991; 88:2204-8. PubMed
30. Kappes, DJ, Strominger, JL, Monos, DS. A novel method for generating stable high-level transfectants involving direct immunomagnetic selection for cell-surface epitopes: expression of HLA class-II genes in HeLa cells. Gene 1991; 108:245-52. PubMed
31. Kappes, DJ, Tonegawa, S. Surface expression of alternative forms of the TCR/CD3 complex. Proc Natl Acad Sci USA 1991; 88:10619-23. PubMed
32. Shin, J, Doyle, C, Yang, Z, Kappes, D, Strominger, JL. Structural features of the cytoplasmic region of CD4 required for internalization. EMBO J 1990; 9:425-34. PubMed
33. Bonneville, M, Ito, K, Krecko, EG, Itohara, S, Kappes, D, Ishida, I, Kanagawa, O, Janeway, CA, Murphy, DB, Tonegawa, S. Recognition of a self major histocompatibility complex TL region product by gamma delta T-cell receptors. Proc Natl Acad Sci USA 1989; 86:5928-32. PubMed
34. Kappes, D, Strominger, JL. Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem 1988; 57:991-1028. PubMed
35. Kappes, DJ, Strominger, JL. Structure and evolution of the HLA class II SX beta gene. Immunogenetics 1986; 24:1-7. PubMed
36. Okada, K, Prentice, HL, Boss, JM, Levy, DJ, Kappes, D, Spies, T, Raghupathy, R, Mengler, RA, Auffray, C, Strominger, JL. SB subregion of the human major histocompatibility complex: gene organization, allelic polymorphism and expression in transformed cells. EMBO J 1985; 4:739-48. PubMed
37. Kappes, DJ, Arnot, D, Okada, K, Strominger, JL. Structure and polymorphism of the HLA class II SB light chain genes. EMBO J 1984; 3:2985-93. PubMed
38. Arnot, D, Lillie, JW, Auffray, C, Kappes, D, Strominger, JL. Inter-locus and intra-allelic polymorphisms of HLA class I antigen gene mRNA. Immunogenetics 1984; 20:237-52. PubMed
39. Collins, T, Korman, AJ, Wake, CT, Boss, JM, Kappes, DJ, Fiers, W, Ault, KA, Gimbrone, MA, Jr., Strominger, JL, Pober, JS. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc Natl Acad Sci USA 1984; 81:4917-21. PubMed
40. Auffray, C, Lillie, JW, Arnot, D, Grossberger, D, Kappes, D, Strominger, JL. Isotypic and allotypic variation of human class II histocompatibility antigen alpha-chain genes. Nature 1984; 308:327-33. PubMed
41. Mullens, IA, Franke, J, Kappes, DJ, Kessin, RH. Developmental regulation of the cyclic-nucleotide-phosphodiesterase mRNA of Dictyostelium discoideum: analysis by cell-free translation and immunoprecipitation. Eur J Biochem 1984; 142:409-15. PubMed
BOOKS, CHAPTERS
42. Arnot, D, Auffray, C, Boss, J, Grossberger, D, Kappes, D, Korman, A, Kuo, J, Lillie, J, Okada, K, Roux Dosseto, M, Schamboeck, A, Strominger, JL. The HLA D region of the human major histocompatibility complex has been created by a large gene expansion. In: Progress in Immunology V, 5th International Congress of Immunology (Yamamura, Y, Tada, T, eds), pp 203 214. Academic Press, Tokyo, 1984.
43. Sorrentino, R, Auffray, C, Boss, J, Grossberger, D, Kappes, D, Levy, D, Lillie, J, Mengler, R, Okada, K, Prentice, H, Raghupathy, R, Spies, T, Strominger, JL. Major histocompatibility complex class II antigens: genes and proteins. In: Monoclonal Antibodies '84: Biological and Clinical Applications (Pinchera, A, Doria, G, Dammacco, F, Bargellesi, A, eds), pp 77-86, 1985.

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Research Interests

My laboratory research program focuses on the treatment of patients with lymphomas, including Hodgkin and non-Hodgkin lymphoma.  I have played a major role in clinical trials for the application of targeted therapeutic agents in lymphoma, with one recent study demonstrating efficacy of the mTOR inhibitor temsirolimus in specific forms of non-mantle cell non-Hodgkin’s lymphoma.  We are also interested in hepatosplenic gamma-delta T-cell lymphoma, a rare peripheral T cell lymphoma that does not respond to standard antracycline-containing chemotherapy: our work is helping to define the clinical features of patients with better versus poorer clinical prognosis.  One of our important goals in clinical research is to develop effective new combination therapies in conjunction with the creation of efficient scoring systems for patient prognosis, to maximize the response of each patient to treatment.

Selected Publications

1. Pozadzides JV, Pro B . Hepatosplenic T-cell lymphoma and TNF- α inhibitors. Expert Rev Hematol. 2009 Dec;2(6):611-4.
2. Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temrolimus has activity in non-mantle cell non-Hodgklin’s lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6.
3. Pro B, Perini G. Central nervous system prophylaxis in peripheral T-cell lymphoma. Blood. 2010 Jul 1;115(26):5427.
4. Ravandi F, Aribi A, O'Brien S, Faderl S, Jones D, Ferrajoli A, Huang X, York S, Pierce S, Wierda W, Kontoyiannis D, Verstovsek S, Pro B, Fayad L, Keating M, Kantarjian H. Phase II Study of Alemtuzumab in Combination With Pentostatin in Patients With T-Cell Neoplasms. J Clin Oncol. 2009 Nov 10;27(32):5425-30.
5. Wang M, Oki Y, Pro B, Romaguera JE, Rodriguez MA, Samaniego F, McLaughlin P, Hagemeister F, Neelapu S, Copeland A, Samuels BI, Loyer EM, Ji Y, Younes A. Phase II Study of Yttrium-90-Ibritumomab Tiuxetan in Patients With Relapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol. 2009 Nov 1;27(31):5213-8.
6. Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, Pro B, Pileri S, Pulsoni A, Soubeyran P, Cortelazzo S, Martinelli G, Martielli M, Rigacci L, Arcaini L, Di Raimondo F, Merli F,Sabattini E, McLaughlin P, Solal-Celigny P. Follicular Lymphoma International Prognostic Index 2: A new index for follicular lymphoma developed by the Interanational Lymphoma Prognostic Factor Project. J Clin Oncol. 2009 Sep 20;27(27):4555-62. Epub 2009 Aug 3.
7. Esmaeli B, McLaughlin P, Pro B, Samaniego F, Gayed I, Hagemeister F, Romaguera J, Cabanillas F, Neelapu SS, Banay R, Fayad L, Wayne Saville M, Kwak LW. Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma. Ann Oncol. 2009 Apr;20(4):709-14. Epub 2009 Jan 15.
8. Tam CS, Bassett R, Ledesma C, Korbling M, Alousi A, Hosing C, Kebraei P, Harrell R, Rondon G, Giralt SA, Anderlini P, Popat U, Pro B, Samuels B, Hagemeister F, Medeiros LJ, Champlin RE, Khouri IF. Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113(18):4144-4152.
9. Falchook GS, Vega F, Dang NH, Samaniego F, Rodriguez MA, Champlin RE, Hosing C, Verstovsek S, Pro B. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann Oncol. 2009 Jun;20(6):1080-5. Epub 2009 Feb 23.
10. Pro B, Leber B, Smith M, Fayad L, Romaguera J, Hagemeister F, Rodriguez A, McLaughlin P, Samaniego F, Zwiebel J, Lopez A, Kwak L, Younes A. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol. 2008 Nov;143(3):355-60. Epub 2008 Sep 1.
11. Leitenberger JJ, Berthelot CN, Polder KD, Pro B, McLaughlin P, Jones D, Duvic M. CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol. 2008 Mar;58(3):480-4.
12. Oki Y, Pro B, Fayad LE, Romaguera J, Samaniego F, Hagemeister F, Neelapu S, McLaughlin P, Goy A, Younes A. Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma. Cancer. 2008 Feb;112(4):831-6.
13. Overman MJ, Feng L, Pro B, McLaughlin P, Hess M, Samaniego F, Younes A, Romaguera JE, Hagemeister FB, Kwak L, Cabanillas F, Rodriguez MA, Fayad LE. The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma. Ann Oncol. 2008 Mar;19(3):553-9. Epub 2007 Dec 13.
14. Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26.
15. Gayed I, Eskandari MF, McLaughlin P, Pro B, Diba R, Esmaeli B. Value of positron emission tomography in staging ocular adnexal lymphomas and evaluating their response to therapy. Ophthalmic Surg Lasers Imaging. 2007;38(4):319-25.
16. Hatef E, Roberts D, McLaughlin P, Pro B, Esmaeli B. Prevalence and nature of systemic involvement and stage at initial examination in patients with orbital and ocular adnexal lymphoma. Arch Ophthalmol. 2007;125(12):1663-7.
17. Jabbour E, Hosing C, Ayers G, Nunez R, Anderlini P, Pro B, Khouri I, Younes A, Hagemeister F, Kwak L, Fayad L. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer. 2007;109(12):2481-9.
18. Dang NH, Fayad L, McLaughlin P, Romaguara JE, Hagemeister F, Goy A, Neelapu S, Samaniego F, Walker PL, Wang M, Rodriguez MA, Tong AT, Pro B. Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma. Br J Haematol. 2007;138(4):502-5, Jul-Aug.
19. Dang NH, Pro B, Hagemeister FB, Samaniego F, Jones D, Samuels BI, Rodriguez MA, Goy A, Romaguera JE, McLaughlin P, Tong AT, Turturro F, Walker PL, Fayad L. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol. 2007;136(3):439-47.
20. Husain A, Roberts D, Pro B, McLaughlin P, Esmaeli B. Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics. Cancer. 2007;110(4):809-15.
21. Soriano AO, Thompson MA, Admirand JH, Fayad LE, Rodriguez AM, Romaguera JE, Hagemeister FB, Pro B. Follicular dendritic cell sarcoma: a report of 14 cases and a review of the literature. Am J Hematol. 2007;82(8):725-8.
22. Oki Y, McLaughlin P, Fayad LE, Pro B, Mansfield PF, Clayman GL, Medeiros LJ, Kwak LW, Srivastava PK, Younes A. Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma. Cancer. 2007;109(1):77-83.
23. Pro B, McLaughlin P. Angioimmunoblastic T-cell lymphoma: still a dismal prognosis with current treatment approaches. Leuk Lymphoma. 2007;48(4):645-6.
24. Younes A, Fayad L, Romaguera J, Pro B, Goy A, Wang M. Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma. Eur J Cancer. 2006;42(17):2976-81.
25. Pro B, Hagemeister FB, McLaughlin P, Romaguera J, Rodriguez MA, Cabanillas F, Tiongson LP, Younes A. Phase 2 study of fludarabine and paclitaxel in patients with recurrent low-grade non-Hodgkin's lymphoma. Leuk Lymphoma. 2006;47(9):1818-21.
26. Pro B, Fayad L, McLaughlin P, Romaguera J, Hagemeister FB, Rodriguez MA, Goy A, Loyer E, Younes A. Pegfilgrastim administered in a single fixed dose is effective in inducing neutrophil count recovery after paclitaxel and topotecan chemotherapy in patients with relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2006;47(3):481-5.
27. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006;24(10):1582-9.
28. Younes A, Pro B, Fayad L. Experience with bortezomib for the treatment of patients with relapsed classical Hodgkin lymphoma. Blood. 2006;107(4):1731-2.
29. Safdar A, Rodriguez MA, Fayad LE, Rodriguez GH, Pro B, Wang M, Romaguera JE, Goy AH, Hagemeister FB, McLaughlin P, Bodey GP, Kwak LW, Raad, II, Couch RB. Dose-related safety and immunogenicity of baculovirus-expressed trivalent influenza vaccine: a double-blind, controlled trial in adult patients with non-Hodgkin B cell lymphoma. J Infect Dis. 2006;194(10):1394-7.
30. Wedgwood A, Pro B, Younes A. The lymphomas: molecular pathways and novel therapeutic targets. Curr Hematol Rep. 2005;4(4):324-334.
31. Anderlini P, Saliba R, Acholonu S, Okoroji GJ, Donato M, Giralt S, Andersson B, Ueno NT, Khouri I, De Lima M, Hosing C, Cohen A, Ippoliti C, Romaguera J, Rodriguez MA, Pro B, Fayad L, Goy A, Younes A, Champlin RE. Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen. Bone Marrow Transplant. 2005;35(10):943-951.
32. Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2005;23(4):667-675.
33. Oki Y, McLaughlin P, Pro B, Hagemeister FB, Bleyer A, Loyer E, Younes A. Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma. Cancer. 2005;104(4):781-787.
34. Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH, Dang NH, Wang M, Beasley V, Medeiros LJ, Katz RL, Gagneja H, Samuels BI, Smith TL, Cabanillas FF. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23(28):7013-23.
35. Khouri IF, Saliba RM, Hosing C, Okoroji GJ, Acholonu S, Anderlini P, Couriel D, De Lima M, Donato ML, Fayad L, Giralt S, Jones R, Korbling M, Maadani F, Manning JT, Pro B, Shpall E, Younes A, McLaughlin P, Champlin RE. Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2005;23(10):2240-2247.
36. Pro B, Younes A, Albitar M, Dang NH, Samaniego F, Romaguera J, McLaughlin P, Hagemeister FB, Rodriguez MA, Clemons M, Cabanillas F. Thalidomide for patients with recurrent lymphoma. Cancer. 2004;100(6):1186-1189.
37. Dang NH, Hagemeister FB, Pro B, McLaughlin P, Romaguera JE, Jones D, Samuels B, Samaniego F, Younes A, Wang M, Goy A, Rodriguez MA, Walker PL, Arredondo Y, Tong AT, Fayad L. Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J Clin Oncol. 2004;22(20):4095-4102.
38. Younes A, Pro B, Robertson MJ, Flinn IW, Romaguera JE, Hagemeister F, Dang NH, Fiumara P, Loyer EM, Cabanillas FF, McLaughlin PW, Rodriguez MA, Samaniego F. Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. Clin Cancer Res. 2004;10(16):5432-5438.
39. Escalon MP, Champlin RE, Saliba RM, Acholonu SA, Hosing C, Fayad L, Giralt S, Ueno NT, Maadani F, Pro B, Donato M, McLaughlin P, Khouri IF. Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol. 2004;22(12):2419-2423.
40. Goy A, Hart S, Pro B, McLaughlin P, Younes A, Dang N, Fayad L, Romaguera J, Cabanillas F, Hagemeister F, Samaniego F, Wang M, Mesina O, Gilles F, Trehu E, Shenkein D. Report of a Phase II Study of Proteasome Inhibitor Bortezomib (VELCADE) in Patients with Relapsed or Refractory Indolent or Aggressive Lymphomas. Blood. 2003;102(11).
41. Pro B, Dang NH. CD26/dipeptidyl peptidase IV and its role in cancer. Histol Histopathol. 2004;19(4):1345-1351.
42. Dabaja BS, McLaughlin P, Ha CS, Pro B, Meyers CA, Seabrooke LF, Wilder RB, Kyritsis AP, Preti HA, Yung WK, Levin V, Cabanillas F, Cox JD. Primary central nervous system lymphoma: Phase I evaluation of infusional bromodeoxyuridine with whole brain accelerated fractionation radiation therapy after chemotherapy. Cancer 2003;98(5):1021-1028.
43. Dang NH, Hagemeister FB, Duvic M, Romaguera JE, Younes A, Jones D, Samuels B, Fayad LE, Pro B, Samaniego F, Sarris A, Goy A, McLaughlin P, Tong AT, Walker PL, Tiongson LP, Smith TL, Huh YO, Morimoto C, Rodriguez MA. Pentostatin in T-non-Hodgkin's lymphomas: efficacy and effect on CD26+ T lymphocytes. Oncol Rep. 2003;10(5):1513-1518.
44. Khouri IF, Lee MS, Saliba RM, Jun G, Fayad L, Younes A, Pro B, Acholonu S, McLaughlin P, Katz RL, Champlin RE. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21(23):4407-4412.
45. Seymour JF, Pro B, Fuller LM, Manning JT, Hagemeister FB, Romaguera J, Rodriguez MA, Ha CS, Smith TL, Ayala A, Hess M, Cox JD, Cabanillas F, McLaughlin P. Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol. 2003;21(11):2115-2122.
46. Dabaja BS, Ha CS, Wilder RB, Pro B, McLaughlin P, Cabanillas F, Cox JD. Importance of esophagogastroduodenoscopy in the evaluation of non-gastrointestinal mucosa-associated lymphoid tissue lymphoma. Cancer J. 2003;9(4):321-324.
47. Romaguera JE, Medeiros LJ, Hagemeister FB, Fayad LE, Rodriguez MA, Pro B, Younes A, McLaughlin P, Goy A, Sarris AH, Dang NH, Samaniego F, Brown HM, Gagneja HK, Cabanillas F. Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer. 2003;97(3):586-591.
48. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003;101(9):3413-3415.
49. Lee HK, Wilder RB, Jones D, Ha CS, Pro B, Rodriguez MA, Romaguera JE, Cabanillas F, Rodriguez J, Cox JD. Outcomes using doxorubicin-based chemotherapy with or without radiotherapy for early-stage peripheral T-cell lymphomas. Leuk Lymphoma. 2002;43(9):1769-1775.
50. Sarris AH, Phan A, Goy A, Romaguera J, Hagemeister FB, Rodriguez MA, McLaughlin P, Pro B, Medeiros LJ, Samuels B, Mesina O, Bleyer AW, Cabanillas F. Irinotecan in relapsed or refractory non-Hodgkin's lymphomas. Indications of activity in a phase II trial. Oncology (Williston Park). 2002;16(8 Suppl 7):27-31.
51. Wilder RB, Rodriguez MA, Medeiros LJ, Tucker SL, Ha CS, Romaguera JE, Pro B, Hess MA, Cabanillas F, Cox JD. International prognostic index-based outcomes for diffuse large B-cell lymphomas. Cancer. 2002;94(12):3083-8.
52. Hagemeister FB, Romaguera J, Pro B, McLaughlin P, Dang N, Cabanillas F. Hodgkin's disease in patients infected with human immunodeficiency virus: frequency, presentation and clinical outcome. Leuk Lymphoma. 2001;41(5-6):535-44.
53. Wilder RB, Rodriguez MA, Ha CS, Pro B, Hess MA, Cabanillas F, Cox JD. Bulky disease is an adverse prognostic factor in patients treated with chemotherapy comprised of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy for aggressive lymphoma. Cancer. 2001;91(12):2440-2446.
54. Sarris AH, Romaguera J, Hagemeister FB, Rodriguez MA, McLaughlin P, Pro B, Younes A, Mesina O, Cabanillas F, Medeiros LJ, Samuels B. Irinotecan in relapsed or refractory non-Hodgkin's lymphoma. Oncology (Williston Park). 7/2001;15(7 Suppl 8):53-6.

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Pathogenesis of Neurotropic Viral Infections

Our laboratory has three main research objectives, all pertaining to viral infections within the central nervous system (CNS) and the diseases that these infections can cause. The first objective is to define how viruses, such as measles, polio and others, are transported to and across the synapse, to result in infection of adjacent neurons. We recently identified a critical role for the neuronal neurotransmitter receptor, neurokinin-1, in trans-synaptic spread of measles virus (MV), and are currently defining interactions between MV components and neuronal molecular motors, such as dynein and kinesin. A major objective of these studies is to ascertain how neurotropic viruses cause disease; using both transgenic mouse models and primary neuronal cultures, we are currently testing whether engagement of crucial cellular factors might account for CNS diseases in the absence of overt neuronal destruction. For example, viral sequestration of neurotransmitter receptors by viral proteins may not only allow the virus to spread among neurons, but could also constitutively trigger neuronal signaling pathways that can lead to neuronal dysfunction.

A second objective of the lab is to characterize the activation, recruitment and function of the host immune response under conditions of CNS infection. Using a novel transgenic mouse model of MV infection of CNS neurons, we have recently defined the signals that recruit immune cells into the infected brain, and have initiated studies to esablish how neurons and T cells interact to result in viral clearance in the absence of neuronal loss. In addition, we have identified key differences between neurons and non-neuronal cells with regard to responsiveness to antiviral cytokines, such as interferons. Such cell-specific responses likely play a critical role in dictating how cells--including tumor cells, which are known to downregulate key immune response proteins--will respond to immune mediators, and may provide key insights into the mechanism underlying the unique cytokine-driven and noncytopathic manner by which the host response resolves some pathogenic challenges.

A third, somewhat new, project within the lab is to develop complex animal models to better understand the complexity of the human response when exposed to multiple pathogens simultaneously. Using our transgenic mouse in which a human MV receptor is restricted to CNS neurons, we developed a model that challenges such mice with MV (infecting neurons within the brain) and periperhally with the natural mouse pathogen, lymphocytic choriomeningitis virus (LCMV; that does not infect the CNS). We also demonstrted massive recrutiment of LCMV-specific T cells into the brain, where no LCMV is present. This "lymhocyte misrecrutiment" results in blood brain barrier damage, edema and death in greater than 50% of doubly challenged mice, as compared to no disease in animals challenged with either pathogen alone. Further exploration of how immune responses interact with each other should result in improved therapeutic modalities to treat immunogenic challenges, including pathogens, allergens and tumors.

Selected Publications

1. O'Donnell LA, Rall GF. "Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin" J Neuroimmune Pharmacol. 2010 Sep;5(3):443-55. PubMed
2. Matullo CM, O'Regan KJ, Hensley H, Curtis M, Rall GF. Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation. J Virol. 2010 Jan;84(1):312-20. PubMed
3. Young VA, Rall GF. Making it to the synapse: measles virus spread in and among neurons. Curr Topics Microbiol Immunol. 2008;330:3-30. PubMed
4. Rose RW, Skipworth JD, Nicolas E, Rall GF. Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J Neuroimmunol. 2007;192:145-156. PubMed
5. Makhortova N, Askovich P, Patterson CE, Gechman LA, Gerard NP, Rall GF. Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology. 2007;362:235-244. PubMed

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Hematopoietic Development and Malignant Transformation

My laboratory is interested in understanding how the specialized cells found in the blood normally develop, a process called hematopoiesis, and how disturbances in this process can contribute to blood cell transformation and cancer. Our research makes use of zebrafish, Danio rerio, a small freshwater fish that has the same spectrum of blood cell types that are present in people and mice. The transparent embryos develop outside the mother's body, each growing from a fertilized egg to an embryo with a beating heart in just 25 hours. We can easily manipulate the genetics of the zebrafish, by inducing random mutations in the DNA, knocking down expression of individual genes, or overexpressing genes of interest. Together, these characteristics make it easy to experimentally manipulate and analyze hematopoiesis, and make zebrafish an ideal model for our studies.

Cancerous cells of hematopoietic origin often have chromosomal deletions, which are thought to contribute to the development of the disease by removing one or more tumor suppressor genes. However, the deleted regions are often very large making it difficult to identify the critical gene or genes. A growing body of evidence has shown that factors essential for the normal development of mature hematopoietic cells can also function as tumor suppressors in blood cell cancers. My laboratory uses the power of zebrafish genetics to discover novel genes that are essential for normal blood cell development and to test their potential to act as tumor suppressors. This strategy allows us to expand our current knowledge about the biology of blood cells and explore zebrafish models of hematopoietic disease, with the goal of revealing important insights to the genesis and progression of blood cell cancers.

Currently, we are exploring four interrelated areas of interest:

1. Hematopoietic gene discovery using random induction of mutations in the genome and assessing the role of the mutated genes in blood cell development
2. Examining genetic networks involved in the development of blood cell cancers by combining different genetic lesions and interrogating the effects on embryonic and adult zebrafish hematopoiesis
3. Developing transgenic zebrafish that label specific subsets of cells with a fluorescent protein, allowing us to study the live development of these cells or purify this population for experimentation

Selected Publications

1. Payne EM, Bolli N, Rhodes J, Abdel-Wahab OI, Levine R, Hedvat CV, Stone R, Khanna-Gupta A, Sun H, Kanki JP, Gazda HT, Beggs AH, Cotter FE, Look AT. Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML. Blood. 2011 Jul 28;118(4):903-15. PubMed
2. Bolli N, Payne EM, Rhodes J, Gjini E, Johnston AB, Guo F, Lee JS, Stewart RA, Kanki JP, Chen AT, Zhou Y, Zon LI, Look AT. cpsf1 is required for definitive HSC survival in zebrafish. Blood. 2011 Apr 14;117(15):3996-4007. PubMed
3. Rhodes J*^, Amsterdam A, Sanda T, Moreau LA, McKenna K, Heinrichs S, Ganem NJ, Ho KW, Neuberg DS, Johnston A, Ahn Y, Kutok JL, Hromas R, Wray J, Lee C, Murphy C, Radtke I, Downing JR, Fleming MD, MacConaill LE, Amatruda JF, Gutierrez A, Galinsky I, Stone RM, Ross EA, Pellman DS, Kanki JP, Look AT. Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression. Mol Cell Biol. 2009 Nov;29(21):5911-22. *Corresponding author. ^Cover image selected for publication by journal. PubMed
4. Rhodes J, Hagen A, Hsu K, Deng M, Liu TX, Look AT, Kanki JP. Interplay of pu.1 and gata-1 determines myelo-erythroid progenitor cell fate in zebrafish. Dev Cell. 2005 Jan;8(1):97-108. PubMed
5. Liu TX, Howlett NG, Deng M, Langenau DM, Hsu K, Rhodes J, Kanki JP, D’Andrea AD, Look AT.  Knockdown of zebrafish Fancd2 causes developmental abnormalities via p53-dependent apoptosis.  Dev Cell. 2003 Dec;5(6):903-14. PubMed

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Research Interests

My research interest is studying the immunologic background of low-grade lymphomas and plasma cell neoplasms and understanding its role in disease progression and outcome.  One way to address this question is to analyze the lymphocytes subtypes in peripheral blood or bone marrow specimens using high-level multicolor flow cytometry.  The advantage of this method is that low volume subpopulations of lymphocytes can be accurately identified and followed during the disease progression.  The presence or absence of different subtypes can be correlated with the clinical outcome and eventually developed into prognostic, persistence or impending relapse markers.  This work will be done in collaboration with Drs. Cohen, Al-Saleem and Campell using fresh peripheral blood and bone marrow samples of patients seen at Fox Chase Cancer Center.  Additionally this method can bring new insights into the immunophenotypic profile of lymphoma cells since they can be analyzed with multiple markers at the same time.  Thus a malignant population can be more reliable be followed in time for evidence of minimal residual disease.    

Selected Publications

1. Gitelson E, Al-Saleem T, Robu VG, Millenson MM, Smith MR. Pediatric nodal marginal zone lymphoma may develop in the adult population. Leuk Lymphoma. 2010 Jan; 51(1):89-94. PubMed
2. Reyes VE Jr, Al-Saleem T, Robu VG, Smith MR. Extranodal NK/T-cell lymphoma nasal type: Efficacy of pegaspargase. Report of two patients from the United Sates and review of literature. Leuk Res. 2010 Jan; 34(1):e50-4. PubMed
3. Faller BA, Robu VG, Borghaei H. Therapy-related acute myelogenous leukemia with an 11q23/MLL translocation following adjuvant cisplatin and vinorelbine for non-small-cell lung cancer. Clin Lung Cancer. 2009 Nov; 10(6):438-40. PubMed

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Hepatitis B and C Viruses – Replication, Antiviral Therapy and Innate Immunity

We are interested in the biology of human pathogenic viruses with an emphasis on mechanisms of viral replication and host-virus interactions that play a role in innate immunity. Our investigations on hepatitis B virus (HBV) lead to the identification of the signals required for reverse transcription of the viral DNA and provided the basis for the current model for hepadnavirus replication. We discovered that the hepatitis B polymerase could be expressed in enzymatically active form in the presence of the heat shock protein 90 complex. Moreover, we demonstrated that recovery from chronic hepatitis B infections requires massive destruction of infected hepatocytes. Investigations on hepatitis C virus (HCV) lead to the discovery that HCV replication could occur in cells of non-hepatic origin in human and mouse cells and hence did neither depend on hepatocyte –or primate-specific factors. We demonstrated that IFN resistance observed in patients was not caused by the emergence of IFN-resistant variants, but rather reflected resistance of hepatocytes to induce an effective antiviral program normally induced by IFN. Furthermore, we discovered that, in contrast to HCV, West Nile virus (WNV) could block the IFN response by inhibiting the phosphorylation of the Janus kinases Jak1 and Tyk2.  

In line with our interest in HBV biology, the goal of our current research effort is to investigate one of the least understood steps in HBV replication: the mechanism by which the viral genome is converted into a covalently closed circular (CCC) DNA form and how intracellular amplification of CCC DNA is regulated. In addition, we are exploring a novel strategy to eliminate CCC DNA from infected cells with the help of sequence specific effector nucleases.

Selected Publications

1. Evans JD, Crown RA, Sohn JA, Seeger C. West Nile Virus infection induces depletion of IFNAR1 protein levels. Viral Immunol. 2011;24:253-263. PubMed
2. Sohn JA, Litwin S, Seeger C. Mechanism for CCC DNA synthesis in hepadnaviruses. PLoS ONE. 2009;4:e8093. PubMed
3. Stiffler JD, Nguyen M, Sohn JA, Liu C, Kaplan D, Seeger C. Focal distribution of hepatitis C virus RNA in infected livers. PLoS ONE. 2009;4:e6661. PubMed
4. Evans JD, Seeger C. Differential effects of mutations in NS4B on West Nile virus replication and inhibition of interferon signaling. J Virol. 2007;81:11809-16. PubMed
5. Guo JT, Hayashi J, Seeger C. West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol. 2005;79:1343-1350. PubMed
6. Hayashi J, Stoyanova R, Seeger C. The transcriptome of HCV replicon expressing cell lines in the presence of alpha interferon. Virology. 2005;335:264-75. PubMed
7. Guo JT, Zhu Q, Seeger C. Cytopathic and noncytopathic interferon responses in cells expressing hepatitis C virus subgenomic replicons. J Virol. 2003;77:10769-79. PubMed
8. Zhu Q, Guo JT, Seeger C. Replication of hepatitis C virus subgenomes in nonhepatic epithelial and mouse hepatoma cells. J Virol. 2003;77:9204-10. PubMed

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Viral Immunology

The overall goals of my laboratory are to determine how vaccines induce the immune system; to identify the mechanisms that contribute to vaccine-mediated protection from disease; and to understand how the interplay of viral gene products with the innate and adaptive immune systems of the host determine susceptibility or resistance to viral disease in immune and non-immune hosts. The importance of these goals in general is that we still do not completely understand how anti-viral vaccines and the immune system protect from viral disease. Hence, our work should yield important insights to develop new anti-viral vaccines and treatments. The role of our work within a Cancer Center is that there is a strong interest in developing anti-cancer vaccines. In our mind, the immune system mainly evolved to combat pathogenic microorganisms but could be coerced to combat cancer if we learn how to manipulate it. Thus, learning how the immune system is best stimulated to eliminate viruses should provide essential insights on how to force it to effectively attack cancer cells. Also, viruses can be used as vectors for anti-viral vaccines. Moreover, many cancers are known or thought to be caused by viruses.

Our work currently focuses on two major research programs. 1) We are studying antigen presentation during viral infections. 2) We are studying viral pathogenesis in a natural host using as a model the laboratory mouse specific pathogen Orthopoxvirus (OPV) ectromelia virus (ECTV), the causative agent of mousepox (the murine parallel of human smallpox).

Selected Publications

1. Remakus S, Rubio D, Ma X, Sette A, Sigal LJ. Memory CD8+ T cells specific for a single immmunodominant or subdominant determinant induced by peptide-dendritic cell immunization protect from an acute lethal viral disease. J Virol. 2012 (Jun 27 - Epub ahead of print). PubMed
2. Fang M, Siciliano NA, Hersperger AR, Roscoe F, Hu A, Ma X, Shamsedeen AR, Eisenlohr LC, Sigal LJ. Perforin-dependent CD4+ T-cell cytotoxicity contributes to control a murine poxvirus infection. Proc Natl Acad Sci USA. 2012;109:9983-8. PubMed
3. Xu R-H, Rubio D, Roscoe F, Krouse TE, Truckenmiller ME, Norbury CC, Hudson PN, Damon IK, Alcami A, Sigal LJ. Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver. PLoS Pathogens. 2012;8:e1002475. PubMed
4. Remakus S, Sigal LJ. Interferon gamma and perforin control the strength, but not the hierarchy, of immunodominance of an anti-viral CD8+ T cell response. J Virol. 2011;85:12578-84. PubMed
5. Fang M, Orr MT, Spee P, Egebjerg T, Lanier LL, Sigal LJ. CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 2011;34:579-89. PubMed
6. Orr MT, Wu J, Fang M, Sigal LJ, Spee P, Egebjerg T, Dissen E, Fossum S, Phillips JH, Lanier LL. Development and function of CD94-deficient natural killer cells. PLoS ONE 2010;5:e15184. PubMed
7. Fang M, Roscoe F, Sigal LJ. Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med 2010;207:2369-81. PubMed
8. Fang M, Sigal LJ. Studying NK cell responses to ectromelia virus infections in mice. In: Natural Killer Cell Protocols, Methods in Molecular Biology Series (Campbell KS, ed), 2nd Edition, Chapter 28, vol. 612, pp. 411-428. Humana Press, 2010.
9. Xu R-H, Remakus S, Ma X, Roscoe F, Sigal LJ. Direct presentation is sufficient for an efficient anti-viral CD8+ T cell response. PLoS Pathog 2010;6:e1000768. PubMed
10. Ma X, Serna A, Xu R-H, Sigal LJ. The amino acids sequences flanking an antigenic determinant can strongly affect MHC class I cross-presentation without altering direct-presentation. J Immunol 2009;182(8):4601-07. PubMed
11. Xu R-H, Cohen M, Tang Y, Lazear E, Whitbeck JC, Eisenberg RJ, Cohen GH, Sigal LJ. The Orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination in a natural host. J Exp Med 2008;205:981-92. PubMed

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Research Overview

The work in our laboratory is focused on obtaining a detailed understanding of the mechanism by which retroviral DNA is integrated into its host cell chromatin, and discovering the epigenetic factors and processes that affect its subsequent expression. Retroviruses are of special interest, not only because they are agents of disease, including cancer, but also because they are important as vehicles for the insertion of desired genes into target cells for scientific investigation and gene therapy. Recently we have also become interested in whether sequences from viruses other than retroviruses have become inserted into vertebrate genomes over an evolutionary time frame, how this may have occurred and, what may be the consequences.  We exploit a broad range of investigational methods in our studies from analyses of protein function, to in vivo studies of viral growth and cell biology. This comprehensive approach provides unique insights, and excellent opportunities for cross-discipline training and collaboration. Our continuing overarching goals are to uncover new information of fundamental importance to both virus and cell biology, and to identify new targets for therapies to treat disease.

We have made exciting progress in our investigation of the molecular structure of retroviral integrases, the enzymes that mediate insertion of viral DNA into the DNA of its host cell. The techniques of small angle X-ray scattering (SAXS) and molecular modeling have been used to obtain the first available information concerning the shapes and structures of integrase monomers, dimers, and tetramers in solution. The resulting models are tested using biochemical crosslinking and mass spectrometry. These structures can now be used to identify points of contact between the protein subunits, as well as between the protein and its DNA substrates. Such information will not only add to our understanding of this complex reaction, but may also suggest new ways to interfere with this activity, which is critical for viral replication.

Together with collaborators in the Systems Biology Group at the Institute for Advanced Study in Princeton, we conducted a systematic analysis of the 48 published vertebrate genomes for sequences related to all known viruses with single-stranded RNA or DNA genomes.  We discovered numerous examples of sequences related to two families of RNA viruses, the Bornaviruses and Filoviruses, which entered 19 vertebrate genomes about 40 million years ago, most likely facilitated by LINE retrotransposons.  We also discovered that the history of integration of sequences related to the small DNA virus families, the Parvoviruses and Circoviruses, spans an even longer evolutionary period from 60 million years ago to recent times.  Some of the sequences from both types of ancient viruses have retained open reading frames, indicating that they have been subject to positive selection and must have provided some advantage to the host or the virus over time.

To understand how integrated viral gene expression is controlled, we have developed a system in which we can monitor high-frequency epigenetic gene silencing of freshly integrated retroviral DNA. We believe that such silencing may reflect a cellular anti-viral response. We have published the results from our proof-of-principle studies using silent “reporter cells” to establish the validity of this system for identification of cellular factors that govern this epigenetic silencing – a phenomenon that is important to our understanding of the antiviral response as well as, the roles of epigenetic factors in normal cell development and cancer. With the help of the Fox Chase Cancer Center High Throughput Screening Facility, we have used this reporter cell population to develop a robust and sensitive siRNA-based high throughput screen to identify specific host factors that participate in the maintenance of epigenetic silencing. Our results to date provide compelling evidence for roles of specific host factors and indicate that they are involved in cooperative and reinforcing interactions that mediate epigenetic silencing.

Selected Publications

1. Peletskaya, E, Andrake, M, Gustchina, A, Merkel, G, Alexandratos, J, Zhou, D, Bojja, RS, Satoh, T, Potapov, M, Kogon, A, Potapov, V, Wlodawer, A, Skalka, AM. Localization of ASV integrase-DNA contacts by site-directed crosslinking and their structural analysis. PLoS One 2011;6:e27751. PubMed
2. Katz RA, Merkel G, Andrake MD, Roder H, Skalka AM. Retroviral integrases promote fraying of viral DNA ends. J Biol Chem. 2011;286:25710-8. PubMed
3. Bojja RS, Andrake MD, Weigand S, Merkel G, Yarychkivska O, Henderson A, Kummerling M, Skalka AM. Architecture of a full-length retroviral integrase monomer and dimer, revealed by small angle X-ray scattering and chemical cross-linking. J Biol Chem. 2011 May 13;286(19):17047-59. Epub 2011 Mar 15. PubMed
4. Belyi VA, Levine AJ, Skalka AM. Sequences from Ancestral Single Stranded DNA Viruses In Vertebrate Genomes: The Parvoviridae And Circoviridae Are More Than 40-50 Million Years Old. J Virol. 2010;84:12458-12462. PubMed
5. Belyi VA, Levine AJ, Skalka AM, 2010 Unexpected Inheritance: Multiple Integrations of Ancient Bornavirus and Ebolavirus/Marburgvirus Sequences in Vertebrate Genomes. PLoS Pathog 6(7): e1001030. doi:10.1371/journal.ppat.1001030. PLoS Pathog
6. Poleshko A, Einarson MB, Adams PD, Zhang R, Skalka AM, Katz RA. Identification of a functional network of human epigenetic silencing factors. J Biol Chem. 2010 Jan 1;285(1):422-33. Epub 2009 Oct 30. PubMed
7. Merkel G, Andrake MD, Ramcharan J, Skalka AM. Oligonucleotide-based assays for integrase activity. Mechanistic and Pharmacological Analyses of HIV-1 Integration. Alan Engelman, ed. Elsevier Editorial Systems for Methods. 2009 Apr;47(4):243-8. Epub 2008 Nov 14. PubMed
8. Katz RA, Daniel R, Skalka AM. Host factors that affect provirus stability and silencing. HIV1 Integrase: Mechanisms Of Action And Inhibitor Design. (Neamati, N, Wand, B, eds.), Chapter 11, pp 141-50. John Wiley and Sons, Inc., UK.
9. Flint SJ, Enquist LW, Racaniello VR, Skalka AM. Principles of Virology, 3rd edition. Vol. II. Pathogenesis and Control of Animal Viruses, 419 pages. ASM Press, Washington DC, 2009
10. Flint SJ, Enquist LW, Racaniello VR, Skalka AM. Principles of Virology, 3rd edition. Vol I. Molecular Biology, 569 pages. ASM Press, Washington DC, 2009.
11. Andrake MD, Sauter MM, Boland K, Goldstein AD, Hussein M, and Skalka AM. Nuclear import of avian sarcoma virus integrase is facilitated by host cell factors. Retrovirology. 2008 August;5:73. PubMed
12. Poleshko A, Palagin I, Zhang R, Boimel P, Castagna C, Adams PD, Skalka AM, and Katz RA. Identification of cellular proteins that maintain retroviral epigenetic silencing: evidence for an antiviral response. J Virol. 2008 December;82(5):2313-23. PubMed
13. Katz RA, Jack-Scott E, Narezkina A, Palagin I, Boimel P, Kulkosky J, Nicolas E, Greger J.G, and Skalka AM. High frequency epigenetic repression and silencing of retroviruses can be antagonized by HDAC inhibitors and transcriptional activators, but uniform reactivation in cell clones is restricted by additional mechanisms. J Virol. 2007 January;81(6):2592-04. PubMed
14. Ramcharan J, Colleluori DM, Merkel G, Andrake MD, and Skalka AM. Mode of Inhibition of HIV-1 integrase by a C-terminal domain-specific monoclonal antibody. Retrovirology. 2006 June; 3:34. PubMed
15. Ramcharan J, Skalka AM. Strategies for identification of HIV-1 integrase inhibitors. Future Virol. 2006 November;1:717-31.
16. Ason B, Knauss DJ, Balke AM, Merkel G, Skalka AM, Reznikoff WS. Targeting Tn5 transposase identifies HIV-1 inhibitors. Antimicrob. Agents Chemother. 2005 April;49:2035-43. PubMed
17. Daniel R, Marusich E, Argyris E, Zhao R Y, Skalka AM, and Pomerantz RJ. Caffeine inhibits HIV-1 transduction of non-dividing cells. J Virol. 2005 February;79(4):2058-65. PubMed
18. Greger JG, Katz RA, Ishov AM, Maul G, and Skalka AM. The cellular protein Daxx interacts with Avian Sarcoma Virus integrase and viral DNA to repress viral transcription. J Virol. 2005 March;79(8):4610-4618, 2005. PubMed
19. Katz RA, Greger JG, and Skalka AM. Effects of cell cycle status on early events in retroviral replication. J Cell Biochem. 2005 April;94:880-89.
20. Skalka AM, and Katz RA. Retroviral DNA integration and the DNA damage response. Cell Death Diff. 2005 August;2:971-78.
21. Daniel R, Ramcharan J, Rogakou E, Taganov KD, Greger JG, Bonner W, Nussenzweig A, Katz RA, and Skalka AM Histone H2AX is phosphorylated at sites of retroviral DNA integration, but is dispensable for post-integration repair. J Biol Chem. 2004 August;279:45810-14.PubMed
22. Narezkina, A., Taganov, K.D., Litwin, S., Stoyanova, R., Hayashi, J., Seeger, C., Skalka, A.M. and Katz, R.A. Genome-wide analyses of avian sarcoma virus integration sites. J Virol. 2004 October;78(21):11656-63.PubMed
23. Daniel R, Katz RA, Greger J, Taganov K, Wu X, Kappes JC, and Skalka, A.M. Evidence that stable retroviral transduction and cell survival following DNA integration depends on components of the NHEJ repair pathway. J Virol. 2004 July;78(16):8573-81.PubMed
24. Daniel R, Myers CB, Taganov K, Greger JG, Merkel G, Weber IT, Harrison RW, and Skalka AM. Characterization of a napthalene-derivative inhibitor of retroviral integrases. AIDS Res Hum Retroviruses. 2004 March;20(2):135-44.PubMed
25. Taganov KD, Cuesta I, Daniel R, Cirillo LA, Katz RA, Zaret KS, and Skalka AM. Integrase-specific enhancement and suppression of retroviral DNA integration by compacted chromatin structure in vitro. J Virol. 2004 April;78(11):5848-55.PubMed
26. Greger J, Katz RA, Taganov K, Rall GF, and Skalka AM. Transduction of terminally differentiated neurons by Avian Sarcoma Virus. J Virol. 2004 April;78(9):4902-06.PubMed

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Research Overview

T lymphocytes recognize and destroy invading pathogens through an assembly of proteins called the T cell antigen receptor (TCR) complex. The TCR has protein subunits that are highly variable and responsible for target recognition (either α/β or γ/δ) and subunits that are invariant proteins and serve to transmit signals (CD3γδε and ζ). This critical protein assembly (the TCR) controls not only the behavior of mature T lymphocytes but also their development in the thymus. My laboratory seeks to understand how T cell development is controlled by the TCR and how these developmental process are corrupted during development of cancer. There are two types of TCR variable proteins, α/β and γ/δ. Utilization of these α/β and γ/δ pairs characterizes two distinct types of T lineages, α/β and γ/δ, respectively. These two T lineages are thought to arise from a single immature precursor in the thymus. We are attempting to identify the cellular factors that are essential for transmitting the signals that direct adoption of these alternate fates (i.e., αβ or γδ). We hypothesize that the genes, which are essential for normal cell development, are also likely to regulate development of cancer. Indeed, we have recently identified such a gene, which encodes a component of the cellular machine responsible for synthesis of all cellular proteins, the ribosome. This component, termed Rpl22, is not only essential for normal T cell development, but also may contribute to development of human T cell cancers termed T acute lymphoblastic leukemia (T-ALL).

Selected Publications

1. Lauritsen JPH, Wong GW, Lee SY, Lefebvre JM, Ciofani M, Rhodes M, Kappes DJ, Zúñiga-Pflücker JC, Wiest DL. Marked induction of the helix-loop-helix protein Id3 promotes the γδ T cell fate and renders their functional maturation Notch-independent. Immunity. 2009;31:565-75. PubMed
2. Anderson SJ, Lauritsen JPH, Hartman M, DiGeorge-Foushee AM, Gerhardt B, Lefebvre JM, Oravecz T, Wiest DL. Defect in ribosomal protein L22 selectively impairs αβ T cell development by activation of a p53-dependent checkpoint. Immunity. 2007;26:759-772. PubMed
3. Ciofani M, Knowles GC, Wiest DL, von Boehmer H, Zúñiga-Pflücker JC. Stage-specific and differential dependency at the αβ/&gamma&delta T lineage bifurcation branchpoint. Immunity. 2006;25:105-16. PubMed
4. Yamasaki S, Ishikawa E, Sakuma M, Ogata K, Sakata-Sogawa K, Hiroshima M, Wiest DL., Tokunaga M, Saito T. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nature Immunology. 2006;7:67-75. PubMed
5. Haks MC, Lefebvre JM, Lauritsen JPH, Carleton MO, Rhodes M, Kappes DJ, Wiest, DL. Attenuation of γδTCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity. 2005;22:595-606. PubMed

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