Angiogenesis is a process of neovascular formation from pre-existing blood vessels , which occurs in multiple and sequential steps of vascular destabilization, angiogenic sprouting, lumen formation and vascular stabilization. The VEGF, FGF, TGF-β, Notch, Hedgehog and WNT signaling cascades orchestrate angiogenesis through the direct or indirect regulation of endothelial cells, basement membrane and coating endothelial cells.
VEGF activates the eNOS, SRC, RAS-ERK and PI3K-AKT signaling cascades through VEGFR2 receptor on endothelial cells, which induce vascular permeability, endothelial migration, proliferation and survival, respectively. Small‑molecule compounds targeting VEGFRs have been developed as anti‑angiogenic therapeutics for cancer and neovascular age-related macular degeneration (AMD). Sunitinib (Sutent) and sorafenib are multi‑kinase inhibitors targeting VEGFR2 and other protein kinases. Sunitinib is applied for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), while sorafenib is applied in RCC and inoperable hepatocellular carcinoma (HCC) treatment.
Drug resistance is the most important clinical problem in cancer treatment using VEFGR inhibitors, as a result of the upregulation of other angiogenic factors, such as FGF2. Dual inhibitors targeting VEGFR/FGFR such as Dovitinib (TKI258) , ponatinib (AP24534) and AZD4547, which induce antitumor effects directly through cancer cells and indirectly through endothelial cells, have been investigated in clinical trials for various types of human cancer.