Novel Approaches Targeting the Vascular Endothelial Growth Factor Axis in Renal Cell Carcinoma

In recent years, functional characterization of the von Hippel- Lindau tumor suppressor, hypoxia-induced factors, and one of their key downstream effectors, the vascular endothelial growth factor (VEGF), has revolutionized treatment of advanced renal cell carcinoma. Therapeutic strategies targeting the ligand itself (VEGF-A) or its receptor (VEGFR2) have proven successful. However, complete remissions are rare, and with time patients invariably suffer disease progression. It is understood that this is due to incomplete suppression of VEGF signaling and/or adaptive up-regulation of non-VEGF-dependent tumor-promoting stimuli. In this article, we review novel VEGF-directed agents that are being developed to address the shortcomings of current targeted drugs for the treatment of advanced renal cell carcinoma. Building on our current understanding of molecular mechanisms behind resistance, examples include next-generation multitarget tyrosine kinase inhibitors, biologics, and other compounds.