Therapeutic application of VEGF inhibitors: future directions and challenges
Angiogenesis, the development of new blood vessels, is a fundamental pathophysiological process.While multiple signaling pathways are implicated in the regulation of vasculogenesis, angiogenesis, differentiation, remodeling of the vessel wall (e.g. Ang-Tie2, PDGF, ephrins, Dll4-notch, etc), the vascular endothelial-derived growth factor (VEGF)-A pathway plays essential roles during development and physiological homeostasis. VEGF-A, belongs to a gene family that also includes VEGF-B, VEGF-C, VEGF-D and placenta growth factor (PlGF). Two tyrosine kinases, VEGFR1 and VEGFR2, bind VEGF-A, but VEGFR2 is the main signaling receptor. VEGF inhibitors have been shown to block tumor growth and neovascularization in numerous preclinical models. We developed a humanized anti-VEGF-A monoclonal antibody (bevacizumab) to test the hypothesis that blocking VEGF-A-induced angiogenesis may result in a clinical benefit in tumor patients. Bevacizumab and other VEGF inhibitors have been approved worldwide for the treatment of several malignancies, most recently in non-small cell lung cancer and renal cell cancer in combination with immune checkpoint inhibitors. The key role of VEGF-A in the pathogenesis of blinding ocular diseases has been established over the past two decades. These efforts resulted in the first effective treatment for neovascular age-related macular degeneration, diabetic macular edema and retinal vein occlusion. Recent advances and challenges will be discussed, including the development in our laboratory of novel VEGF inhibitors that have high affinity for heparan sulfate proteoglycans in the vitreous, which results in longer half-life and requirement of less frequent intravitreal administrations.