Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma.
OBJECTIVE
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.


CONCLUSIONS
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.
Rini
Brian I
BI
University of California San Francisco Comprehensive Cancer Center, CA, USA. brini@medicine.ucsf.edu
Small
Eric J
EJ
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab; D001695:Biology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human