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Genitourinary Cancer

Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies

^aUniversity of Colorado Health Sciences Center, Denver, Colorado, USA; ^bMedical University of South Carolina, Division of Hematology-Oncology, Charleston, South Carolina, USA

Key Words. Carcinoma • Renal cell • VEGF • Protein tyrosine kinases • mTOR protein • Interferons

Correspondence: Harry A. Drabkin, M.D., Division of Hematology/Oncology, Medical University of South Carolina, P.O. Box 250623, 96 Jonathan Lucas Street, Charleston, South Carolina 29425, USA. Telephone: 843-792-8297; Fax: 843-792-0644; e-mail: drabkin{at}musc.edu

Disclosure: H.A.D. served on the advisory board for sorafenib and for Wyeth. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

Renal cell carcinoma (RCC) affects 38,000 individuals in the U.S. yearly. Seventy-five percent of cases are clear-cell carcinomas, and a majority is driven by dysfunction of the von Hippel-Lindau (VHL) gene. VHL loss of function and other non-VHL pathways leading to RCC share aberrant activation of the hypoxic response, such as upregulation of vascular endothelial growth factor (VEGF) and consequent neoangiogenesis. Metastatic RCC has been notoriously resistant to therapy. For decades, its treatment has been based on nephrectomy and limited use of toxic and often inefficient immunotherapy with interleukin-2 or interferon-. However, new biologic agents are beginning to break the resistance barrier. Small-molecule multikinase inhibitors that target VEGF receptors (sunitinib and sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients. The anti-VEGF antibody bevacizumab enhances the response rate and prolongs disease control when added to interferon-. Temsirolimus, a mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. Despite three new drugs being approved for RCC in the past 2 years, responses are mostly partial and of limited duration. Multiple new drugs and drug combinations are undergoing clinical trials and will likely impact the treatment of RCC in future years. Compounds found to be active in the metastatic setting are now being tried in earlier stage disease in an attempt to improve curability. However, no method has yet been validated to predict patient response to these newer treatments.

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