Robert G Uzzo, MD, FACS
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.