Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma.

Published

Journal Article (Review)

Frequent loss of the von Hippel-Lindau (VHL) gene product in conventional-type renal cell carcinoma results in constitutive expression of proangiogenic growth factors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). VEGF and PDGF function in a paracrine manner to stimulate tumor angiogenesis that results in a hypervascular phenotype. Dependency on this hypervascularity is underscored by the recent clinical efficacy shown by inhibition of the VEGF pathway. Most strategies that primarily target the VEGF pathway (neutralizing antibodies or receptor tyrosine kinase inhibitors) result in objective tumor responses in < or =10% of cases but show a significant delay in time to disease progression. In contrast, two multitargeted receptor tyrosine kinase inhibitors that target both VEGF and PDGF receptors (sunitinib and AG013736) have shown > or =40% objective responses with clinically important duration. Several hypotheses may explain the discrepancy of these response rates from other strategies in the class, including the synergistic effects of dual inhibition of VEGF and PDGF receptors, supported by preclinical studies. Ultimately, further clinical investigations with pharmacodynamic and correlative science end points are needed to clarify the mechanisms of action and resistance to build on the biological and clinical effects of these multitargeted agents.

Full Text

Duke Authors

Cited Authors

  • George, DJ

Published Date

  • January 15, 2007

Published In

Volume / Issue

  • 13 / 2 Pt 2

Start / End Page

  • 753s - 757s

PubMed ID

  • 17255305

Pubmed Central ID

  • 17255305

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-06-2044

Language

  • eng

Conference Location

  • United States