Faculty Summaries
Alfonso Bellacosa, MD, PhD
Alfonso Bellacosa, MD, PhD
Professor
  • Adjunct Associate Professor, Department of Biochemistry, Drexel University College of Medicine
  • Adjunct Professor, College of Science and Technology, Temple University
  • Adjunct Associate Professor, Department of Microbiology and Immunology, Temple University School of Medicine
alfonso.bellacosa@fccc.edu
Office Phone: 215-728-4012
Lab Phone: 215-728-4013
Fax: 215-214-1590
Office: P3041
Lab: P3023
  • 1. Role of DNA Repair in Genomic and Epigenomic Stability

    Although genetic instability is almost invariably associated with cancer, it is unclear if an increase in the mutation rate is necessary in tumorigenesis. We are trying to determine the role of base excision repair activities in maintaining genomic stability at the level of CpG sites. CpG sites are prone to mutations as a consequence of spontaneous deamination of cytosine and 5-methylcytosine, leading to U:G and T:G mismatches, respectively. We are studying two mammalian base excision repair enzymes that remove the offending uracil and thymine from G:U and G:T mismatches, MBD4/MED1 and TDG, thus preventing CpG to CpA (or CpG to TpG) transition mutations. Recent work from our and other laboratories indicates that MBD4/MED1 and TDG have an additional role in transcription, by affecting the patterns of methylation at CpG sites (or epigenomic stability). We are studying the impact of MBD4/MED1 and TDG inactivation in development and in human cancer.

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  • 2. Inhibition of Ciliogenesis as a Candidate Therapy for Medulloblastoma

    Medulloblastoma is a brain tumor with the highest incidence in childhood among all the primary central nervous tumors. It is highly invasive and has a tendency to disseminate throughout the central nervous system in the early phase of its course. In medulloblastoma, “sonic hedgehog” (SHH) signaling is frequently altered; specifically, hyperactivation of SHH signaling leads to uncontrolled cell proliferation. Thus, inactivation or inhibition of SHH may represent a novel strategy to treat medulloblastoma. We showed that the protein Ift122, involved in the biogenesis of primary cilia, was necessary for SHH activity. In this project, we are trying to inactivate Ift122 to block formation of cilia and interrupt the tumorigenic SHH signaling.

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  • 3. Identification of Early Molecular Changes in Tumorigenesis

    Whether a mutator phenotype takes place or not in the developing cancer cell, ultimately, mutations accumulate at critical oncogenes and tumor suppressor genes that regulate cell cycle progression, death and differentiation. In an effort to identify the earliest molecular changes in tumorigenesis, prior to formation of even benign lesions, we found that morphologically normal cells heterozygous for tumor suppressor gene mutations (i.e. single-hit cells) harbor early molecular changes that resemble those found later in cancer cells, such as activation of the PI3K/AKT/mTOR axis. We are continuing the characterization of these changes, examining their mechanistic relevance in terms of alterations in signaling pathways, and evaluating the possibility that they could represent early biomarkers of cancer risk and molecular targets for strategies of chemopreventive intervention.

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