Vascular Endothelial Growth Factor–Targeted Therapies in Advanced Renal Cell Carcinoma

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Von Hippel-Lindau and VEGF

First isolated in the hereditary syndrome Von Hippel-Lindau (VHL) disease, the importance of the VHL tumor-suppressor gene emerged in sporadic clear cell RCC.1, 2, 3 VHL gene inactivation has been observed in 84% to 98% of sporadic RCCs.4, 5, 6 These observations are specific to clear cell RCC histology; VHL mutations have not been observed in other subtypes of RCC. Biallellic VHL gene inactivation has, therefore, been considered a key event in clear cell RCC oncogenesis according to the

Bevacizumab

Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) is a recombinant monoclonal antibody (mAb) IgG1 antibody that has been developed for humans from murine anti-VEGF mAb A4.6.1. The murine mAb A4.6.1 is specific for human VEGF, binding to all of the known isoforms of the ligand (eg, VEGF121, VEGF165, VEGF181, VEGF206). It is formed through alternative gene splicing, preventing it from binding to VEGFRs on vascular endothelial cells. In 1997, murine anti-VEGF mAb A4.6.1 was adapted

VEGFR tyrosine kinase inhibitors

Better understanding of the biology of VEGF and its related pathway in the pathogenesis of RCC led to the era of small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib, and axitinib and tivozanib, which are currently being evaluated), which block the intracellular domain of the VEGFR, in the management of RCC.

Summary

VEGF targeted therapy is the main treatment of mRCC in 2011. Both selective VEGF blockade using bevacizumab and VEGF receptor inhibition are effective and have almost similar activities, but have different potencies (Tables 3 and 4) and toxicity profiles (Table 5). Off-target effects are important to consider for treatment decisions, and ongoing and future studies will be critical for choosing between currently available drugs (bevacizumab, sorafenib, sunitinib, pazopanib) and upcoming new

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    These two authors are co–first authors and have contributed equally to the work.

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