Targeting angiogenesis with oral agents

The advent of molecular targeted therapies through a better understanding of the cancer cell molecular circuitry has revolutionized treatment approaches in oncology. Targeting neovascularization offers tremendous potentialities (1). There is a finely regulated equilibrium between numerous natural antiangiogenic and proangiogenic factors. The tumor angiogenic phenotype is characterized by high microvessel density in the tumor with elevated vascular endothelial growth factor (VEGF) levels and is usually correlated with a worse prognosis. During angiogenesis, endothelial cells are stimulated by various growth factors that bind to membranous receptors, essentially tyrosine kinase receptors (TKRs). The TKRs directly involved in angiogenesis include receptors for VEGF, FGF, PDGF, angiopoïetin-1 (Ang-1) Ang-2, hepatocyte growth factor (HGF), Eph, and receptors belonging to the epithelial growth factor family. These receptors are expressed by endothelial cells or pericytes but not by tumor cells that secrete ligands. VEGF is the most potent inducer of angiogenesis. VEGF-A, commonly referred to as VEGF, can be induced by hypoxia and hypoxia-inducible factor 1 (HIF-1), inactivation of the von Hippel-Lindau (vHL) tumor suppressor gene, and a number of cytokines and growth factors, including platelet-derived growth factor (PDGF), tumor necrosis factor a (TNF-a), and transforming growth factor b (TGF-b). VEGF binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR), which are the major mediators of the mitogenesis-, angiogenesis-, and permeability-enhancing effects of VEGF. A large number of oral antiangiogenic agents, particularly TKR inhibitors, are currently under clinical development, with marketing approvals already granted for some of them (sunitinib and sorafenib). This review focuses on the most promising and advanced among them, with special emphasis on the VEGFR pathway (Tables 1 and 2).