Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma

Since late 2005 six new drugs have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma (RCC). However, the similarity of these agents with regard to mechanism of action makes it unclear if each agent has unique clinical utility. This flurry of drug development activity stems from the understanding of the central role that loss of von Hippel Lindau (VHL) gene function plays in the pathophysiology of clear cell RCC. The first agent to establish the therapeutic value of targeting the downstream consequences of VHL loss of function was a vascular endothelial growth factor (VEGF) directed monoclonal antibody, bevacizumab. Following the initial observations with bevacizumab, three VEGF receptor (VEGFR) tyrosine kinase inhibitors, with varied spectra beyond VEGFR, have been successfully developed clinically. Unanticipated clinical activity was observed with inhibitors of mTOR, a central component of the nutrient-sensing PI3 kinase pathway, in RCC. Subsequent work identified that mTOR also regulates the expression of hypoxia inducible factor (HIF), which is regulated by VHL outside of the setting of inactivating mutations or deletions. This appears to tie all of the six approved therapies to the direct consequences of loss of VHL function in clear cell RCC. It remains poorly understood to what extent these therapies differ from one another. Although the outcome of patients with metastatic RCC has been substantially altered with administration of the currently available therapies, the proper selection of currently available therapy, rational development of agents with novel mechanism of action and development of predictive biomarkers of response remains a challenge.