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Overcoming VEGF resistance in renal cancer. biologic and therapeutic implications

Sarmad Sadeghi, Jorge A Garcia

Over the last few years, significant progress in the management of metastatic renal cell carcinoma (RCC) has been made. Although currently US FDA-approved therapies have shown dramatic efficacy, none of these have led to complete and durable responses. In addition to their complex side-effect profile, all patients eventually developed progressive disease and ultimately succumbed to their disease. Multiple clinical trials have addressed the importance of sequential therapy in RCC; however, none of them have built molecular correlative studies that would allow us to define the process of resistant disease. Emerging preclinical data demonstrate that VEGF remains an important driver in the resistance setting. Newer pathways such as the Tie2/ANG-2 pathway also appear to contribute to the resistant process. Future clinical trials will incorporate some of these concepts with the goal of providing a more rational selection of sequential therapies in metastatic RCC.