Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma.
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.
George
Daniel J
DJ
Department of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke University Medical Center, Durham, NC 27705, USA. daniel.george@duke.edu
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D000077210:Sunitinib