This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by George, D. J. Search for Related Content PubMed PubMed Citation Articles by George, D. J.

Phase 2 Studies of Sunitinib and AG013736 in Patients with Cytokine-Refractory Renal Cell Carcinoma

Author's Affiliation: Department of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Daniel J. George, Department of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke University Medical Center, Durham, NC 27705. Phone: 978-318-9582; Fax: 1-978-318-9583; E-mail: daniel.george{at}duke.edu.

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 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 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.

This article has been cited by other articles:

				M. R. Chintalapudi, M. Markiewicz, N. Kose, V. Dammai, K. J. Champion, R. S. Hoda, M. Trojanowska, and T. Hsu Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells Carcinogenesis, April 1, 2008; 29(4): 696 - 703. [Abstract] [Full Text] [PDF]