Originally published as JCO Early Release 10.1200/JCO.2005.01.186 on November 8 2004

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rini, B. I. Articles by Small, E. J. Search for Related Content PubMed PubMed Citation Articles by Rini, B. I. Articles by Small, E. J.

Biology and Clinical Development of Vascular Endothelial Growth Factor–Targeted Therapy in Renal Cell Carcinoma

Brian I. Rini, Eric J. Small

From the University of California San Francisco Comprehensive Cancer Center, San Francisco, CA

Address reprint requests to Brian I. Rini, MD, 1600 Divisadero, Room A717, San Francisco, CA 94115; e-mail: brini{at}medicine.ucsf.edu.

PURPOSE: To review the biology of renal cell carcinoma (RCC) leading to vascular endothelial growth factor (VEGF) overexpression and the clinical results of VEGF blockade in metastatic RCC.

METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken.

RESULTS: VEGF is the major proangiogenic protein that exerts a biologic effect through interaction with cellular receptors. The majority of sporadic clear-cell RCC tumors are characterized by VHL tumor suppressor gene inactivation. The resulting VHL gene silencing leads to VEGF overexpression. An antibody to VEGF (bevacizumab) has demonstrated a significant prolongation of time to disease progression compared with placebo in patients with metastatic RCC. Small molecules with inhibitory effects against the VEGF receptor have undergone initial clinical testing in metastatic RCC with substantial objective response rates.

CONCLUSION: Therapeutic targeting of VEGF in RCC has strong biologic rationale and preliminary clinical efficacy. Further investigation will determine the optimal timing, sequence, and utility of these agents in RCC.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

This article has been cited by other articles:

				B. I. Rini, M. D. Michaelson, J. E. Rosenberg, R. M. Bukowski, J. A. Sosman, W. M. Stadler, T. E. Hutson, K. Margolin, C. S. Harmon, S. E. DePrimo, et al. Antitumor Activity and Biomarker Analysis of Sunitinib in Patients With Bevacizumab-Refractory Metastatic Renal Cell Carcinoma J. Clin. Oncol., August 1, 2008; 26(22): 3743 - 3748. [Abstract] [Full Text] [PDF]

				B. Melichar, P. Koralewski, A. Ravaud, A. Pluzanska, S. Bracarda, C. Szczylik, C. Chevreau, M. Filipek, R. Delva, E. Sevin, et al. First-line bevacizumab combined with reduced dose interferon-{alpha}2a is active in patients with metastatic renal cell carcinoma Ann. Onc., August 1, 2008; 19(8): 1470 - 1476. [Abstract] [Full Text] [PDF]

				C. Salvador, B. Li, R. Hansen, D. E. Cramer, M. Kong, and J. Yan Yeast-Derived {beta}-Glucan Augments the Therapeutic Efficacy Mediated by Anti-Vascular Endothelial Growth Factor Monoclonal Antibody in Human Carcinoma Xenograft Models Clin. Cancer Res., February 15, 2008; 14(4): 1239 - 1247. [Abstract] [Full Text] [PDF]

				L. J. Costa and H. A. Drabkin Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies Oncologist, December 1, 2007; 12(12): 1404 - 1415. [Abstract] [Full Text] [PDF]

				B. H. O'Neil and A. P. Venook Hepatocellular Carcinoma: The Role of the North American GI Steering Committee Hepatobiliary Task Force and the Advent of Effective Drug Therapy Oncologist, December 1, 2007; 12(12): 1425 - 1432. [Abstract] [Full Text] [PDF]

				J. A. Gollob, W. K. Rathmell, T. M. Richmond, C. B. Marino, E. K. Miller, G. Grigson, C. Watkins, L. Gu, B. L. Peterson, and J. J. Wright Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer J. Clin. Oncol., August 1, 2007; 25(22): 3288 - 3295. [Abstract] [Full Text] [PDF]

				L. S. Angelo and R. Kurzrock Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators Clin. Cancer Res., May 15, 2007; 13(10): 2825 - 2830. [Abstract] [Full Text] [PDF]

				A. Haferkamp and M. Hohenfellner Medical treatment options in patients with metastatic renal cell carcinoma Nephrol. Dial. Transplant., April 1, 2007; 22(4): 996 - 999. [Full Text] [PDF]

				J. A. Garcia and B. I. Rini Recent Progress in the Management of Advanced Renal Cell Carcinoma CA Cancer J Clin, March 1, 2007; 57(2): 112 - 125. [Abstract] [Full Text] [PDF]

				B. I. Rini Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions Clin. Cancer Res., February 15, 2007; 13(4): 1098 - 1106. [Abstract] [Full Text] [PDF]

				C. Simonelli, R. Talamini, A. Bearz, M. Berretta, S. Spazzapan, P. Monini, C. Sgadari, I. Sartor, B. Ensoli, and U. Tirelli Interleukin-2 continuous infusion and angiogenesis surrogate markers in metastatic renal cell carcinoma Ann. Onc., August 1, 2006; 17(8): 1335 - 1336. [Full Text] [PDF]

				D. H. Albert, P. Tapang, T. J. Magoc, L. J. Pease, D. R. Reuter, R.-Q. Wei, J. Li, J. Guo, P. F. Bousquet, N. S. Ghoreishi-Haack, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther., April 1, 2006; 5(4): 995 - 1006. [Abstract] [Full Text] [PDF]

				N. J. Vogelzang Treatment Options in Metastatic Renal Carcinoma: An Embarrassment of Riches J. Clin. Oncol., January 1, 2006; 24(1): 1 - 3. [Full Text] [PDF]

				A. Arora and E. M. Scholar Role of Tyrosine Kinase Inhibitors in Cancer Therapy J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 971 - 979. [Abstract] [Full Text] [PDF]