Inhibition of vascular endothelial growth factor receptor signaling in angiogenic tumor vasculature.

Neovascularization takes place in a large number of pathologies, including cancer. Significant effort has been invested in the development of agents that can inhibit this process, and an increasing number of such agents, known as antiangiogenic drugs, are entering clinical trials or being approved for clinical use. The key players involved in the development and maintenance of tumor neovasculature are vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), and therefore VEGF/VEGFR signaling pathways have been a focus of anticancer therapies for several decades. This review focuses on two main approaches designed to selectively target VEGFRs, inhibiting VEGFR with small molecule inhibitors of receptor tyrosine kinase activity and inhibiting the binding of VEGF to VEGFRs with specific antibodies or soluble decoy VEGF receptors. The major problem with these strategies is that they appeared to be effective only in relatively small and unpredictable subsets of patients. An alternative approach would be to subvert VEGFR for intracellular delivery of cytotoxic molecules. We describe here one such molecule, SLT-VEGF, a fusion protein containing VEGF121 and the highly cytotoxic catalytic subunit of Shiga-like toxin.