Targeted RCC therapies create new role for urologists

September 1, 2006

Within the past year, enormous strides have been made in the treatment of renal cell carcinoma, particularly in the pharmacotherapeutic arena. To date, two new drugs have received FDA approval, and other promising agents are in development. As research provides new insights into the nature of RCC and its treatment, the role of the urologist in patient management is evolving quickly.

Within the past year, enormous strides have been made in the treatment of renal cell carcinoma, particularly in the pharmacotherapeutic arena. To date, two new drugs have received FDA approval, and other promising agents are in development. As research provides new insights into the nature of RCC and its treatment, the role of the urologist in patient management is evolving quickly. In this interview, Robert G. Uzzo, MD, discusses new kidney cancer drugs and their potential impact on urologists' approach to this disease. Dr. Uzzo is an attending surgeon, department of urologic oncology, Fox Chase Cancer Center, Philadelphia. The interview was conducted by former UT Editorial Consultant Robert C. Flanigan, MD, professor and chairman, department of urology, Loyola University, Maywood, IL.

Q. Please talk about the new drugs, including their mechanisms of action.

A. When you think about targeted therapies, it all starts with understanding what the target is and how we got there. Over the past 4 decades, there's been a great deal of research from many labs and individuals doing research on the pathways that relate to kidney cancer progression. I like to tell patients that we know more about the molecular biology of kidney cancer than we do about any other solid tumor. We know what the sentinel genetic mutations are and, at least in the case of clear-cell carcinoma, we know what the important aspects of the pathway are. We now know that perturbations in that pathway can be used for therapeutic benefit.

It starts with the von Hippel-Lindau gene on the short arm of the third chromosome. It is responsible for the VHL protein, which then binds to a number of other proteins in the Elongin and Cullin families. The hypoxia-inducible factors are a group of transcriptional factors that therefore bind the VHL protein complex. When VHL is mutated, the hypoxia-inducible factor is left to translocate into the nucleus, where it binds with its promoter regions and up-regulates its dependent genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), glucose transport proteins, and chemokines, such as CXCR4.