Hypoxia-regulated genes such as
vascular endothelial growth factor (
VEGF) and
epidermal growth factor (
EGF) are both important for tumour progression in
renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-
VEGF antibody demonstrate a delay in the time to
disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of
VEGF, FLT3, KIT and
platelet-derived growth factor receptor tyrosine kinases, such as
sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with
sorafenib, an inhibitor of multiple
tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the
mammalian target of rapamycin. Conversely,
EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and
imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted
therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of
hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted
therapy could lead to a new standard of care for RCC.