Vladimir Kolenko, MD, PhD

Vladimir Kolenko, MD, PhD
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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
Learn more about Research Volunteering.

Associate Research Professor

Research Program

Language(s) Other than English

  • Russian

Educational Background

  • PhD, Institute for Vaccines and Sera, Moscow, Russia, 1990
  • MD, Academy of Medicine, Moscow, Russia, 1986 

People

  • Rushaniya Fazliyeva, BA
    Scientific Technician
    W246

Research Interests

  • Resistance to multitargeted receptor tyrosine kinase inhibitors in renal cell carcinoma.
  • Resistance to androgen deprivation therapy in prostate cancer.
  • Non-NAD-like PARP-1 inhibitors as novel therapeutic agents for the treatment of genitourinary cancers.

Lab Overview

My research efforts span the basic and the translational sciences. The work in our lab focuses on understanding the process of prostate and renal carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers.  My research interests include mechanisms of resistance to tyrosine kinase inhibitors and androgen deprivation therapy, as well as development of novel and repurposing of existing pharmacological agents.

Lab Description

My research efforts span the basic and the translational sciences. The work in our lab focuses on understanding the process of prostate and renal carcinogenesis and assessing novel therapeutic regimens for the treatment of urological cancers.  My research interests include mechanisms of resistance to tyrosine kinase inhibitors and androgen deprivation therapy, as well as development of novel and repurposing of existing pharmacological agents.

As part of our work, we study mechanisms of resistance to multi-targeted tyrosine kinase inhibitors (TKIs) in renal cell carcinoma (RCC). The ability of TKIs to inhibit angiogenesis is well-established. We and others have demonstrated that in addition to the inhibition of angiogenesis, TKIs also manifest a direct cytotoxic effect on tumor cells. Importantly, the high response rate is usually attributed to a direct effect of TKIs on tumor cells. Our group showed that loss of the tumor suppressor phosphatase and tensin homolog (PTEN) expression and subsequent activation of Akt/mTOR signaling confers resistance to TKIs in RCC cells. Our recent studies demonstrate that lipoprotein-derived cholesterol is capable of increasing activation of Akt/mTOR signaling in RCC cells and counteracting the antitumor activity of TKIs. Furthermore, RCC xenograft tumors resist treatment with TKIs in mice fed a high-fat/high-cholesterol diet. Critically, our findings indicate that all major lipoproteins (i.e. HDL, LDL, and VLDL) have a comparable ability to supply cellular cholesterol and are equally effective in counteracting the antitumor activity of TKIs. These findings suggest that RCC cells have redundant mechanisms of cholesterol acquisition to ensure its adequate supply. Therefore, only concomitant targeting of all sources of cholesterol acquisition or common routes of intracellular cholesterol trafficking is postulated to have therapeutic benefits. We plan to address this issue by targeting endolysosomal cholesterol transport in tumor cells based on the fact that this is a point where trafficking routes of different lipoproteins converge.  Also, our most recent studies suggest that in addition to promoting prostate cancer (PC) progression as a substrate for de novo androgen synthesis, lipoprotein-derived cholesterol contributes to the development of castration-resistant phenotype and resistance to androgen deprivation therapy by triggering androgen-independent pro-tumorigenic signaling in PC cells.

Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes, that are important for fatty acid and cholesterol synthesis, as well as signaling functions, through serving as the acetyl group donor for protein acetylation. The two major enzymes that produce acetyl-CoA are ATP-citrate lyase (ACLY), the main enzyme responsible for cytosolic acetyl-CoA synthesis, which generates acetyl-CoA from mitochondria-derived citrate, and acetyl-CoA synthetase 2 (ACSS2), which produces acetyl-CoA from acetate. Both ACLY and ACSS2 are aberrantly expressed in PC. Chromatin remodeling via histone acetylation facilitates androgen receptor (AR) transcriptional activity. Besides canonical histone acetylation activity, histone acetyltransferase p300/CBP acetylates the AR. Acetylation of AR enhances coactivator binding, increases its transcriptional activity and promotes growth of PC cells. We are currently testing the novel hypothesis that resistance to androgen deprivation therapy is associated with the aberrant activation of the acetyl-CoA pathway in PC cells. This hypothesis is supported by our preliminary studies showing that 1) The addition of exogenous acetyl-CoA, or its precursor acetate, diminishes the anti-AR activity of abiraterone and enzalutamide; 2) Treatment with enzalutamide and abiraterone significantly elevates intracellular levels of acetyl-CoA in PC cells; 3) The expression of ACLY, the main enzyme responsible for cytosolic acetyl-CoA synthesis, is substantially elevated in castration-resistant C4-2B cells compared with parental androgen-dependent LNCaP cells; 4) Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation.

Poly(ADP-ribose) polymerase 1 (PARP-1)-regulated signaling contributes to the initiation and progression of various human malignancies. Importantly, PARP-1 enhances the stability and accumulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), arguably the most common driving factors in renal carcinogenesis. PARP-1 also functions as a transcriptional coactivator of the HIF coactivator p300 and nuclear factor-kappaB (NF-kappaB). Our studies demonstrate that levels of pADPr, a marker of PARP-1 activity, are significantly elevated in primary and metastatic RCC tissue specimens compared with normal kidney tissue samples. In collaboration with Alexei Tulin, PhD (University of North Dakota), we have developed a novel class of PARP-1 inhibitors by targeting the histone-dependent route of PARP-1 activation, a mechanism that is unique to PARP-1. Histone-dependent PARP-1 inhibitors demonstrate superior specificity and antitumor activity compared with the classical NAD-like PARP-1 inhibitors in cell and animal models of human RCC.

Selected Publications

Makhov P, Naito S, Haifler M, Kutikov A, Boumber Y, Uzzo RG, Kolenko V. The convergent roles of NF-kB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma. Cell Death & Disease. 9(3):374, 2018.

Makhov P, Joshi S, Ghatalia P, Kutikov A, Uzzo GU, Kolenko V. Resistance to systemic therapies in clear cell renal cell carcinoma: mechanisms and management strategies. Mol Cancer Ther. 17(7):1355-1364, 2018.

Naito S, Ichiyanagi O, Ito H, Kabasawa T, Kanno H, Narisawa T, Fukuhara H, Yagi M, Kurota Y, Yamagishi A, Sakurai T, Nishida H, Kawazoe H, Yamanobe T, Kato T, Makhov P, Kolenko V, Yamakawa M, Tsuchiya N. Expression of total and phospho 4EBP1 in metastatic and non‑metastatic renal cell carcinoma. Oncology Letters. 17(4):3910-3918, 2019.

Karpova Y, Wu C, Divan A, McDonnell M, Hewlett E, Makhov P, Gordon J, Ye M, Reitz A, Childers W, Skorski T,  Kolenko V, Tulin A. Non-NAD-like PARP-1 inhibitors in prostate cancer treatment. Biochemical Pharmacology. 167:149-162, 2019.

Zhao Z, Kurimchak A, Nikonova A, Feiser F, Varughese T, Johnson K, Makhov P, Lindskog C, Kolenko V, Golemis E, Duncan J, Grana X. PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization. Oncogenesis. 8(12):72, 2019.

Makhov P, Uzzo RG, Tulin AV, Kolenko V. Histone-dependent PARP-1 inhibitors: A novel therapeutic modality for the treatment of prostate and renal cancers. Urological Oncology. May 8;S1078-1439(20):30145-9, 2020.

Makhov P, Sohn JA, Serebriiskii IG, Fazliyeva R, Khazak V, Boumber Y, Uzzo RG, Kolenko V. CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinoma. British Journal of Cancer. Sep 24, 2020.

Additional Publications

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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
Learn more about Research Volunteering.