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Critical Reviews™ in Oncogenesis
Antiangiogenic Therapies Targeting the Vascular Endothelia Growth Factor Signaling System
Royal Melbourne Hospital, Western Hospital, and Ludwig Institute for Cancer Research, Parkville, Victoria, Australia
Royal Melbourne Hospital, Peter McCallum Cancer Center, and Ludwig Institute for Cancer Research, Parkville, Victoria, Australia
Angiogenesis is critical to the growth of human tumors and the development of metastasis. Amongst the many proangiogenic mechanisms identified, the vascular endothelial growth factor (VEGF) signaling pathway has been implicated as the key regulator of tumor neovascularisation. Various therapeutic agents targeting the VEGF pathway have been successfully developed, with many now approved and in routine clinical use. In general, VEGF-mediated angiogenesis can be inhibited by 2 approaches: antibodies directed against VEGF ligands or VEGF receptors (VEGFRs) and tyrosine kinase inhibitors targeting the VEGFRs. Thus far, clinical benefits achieved with VEGF-targeted agents are limited by their modest efficacy and the development of resistance. With no shortage of drugs in development, the lack of well-validated biomarkers to predict for response or resistance to VEGF-directed therapies is now becoming a key factor limiting the further rational development of this class of anticancer agent. This review discusses the biology of VEGF signaling, the clinical efficacy of VEGF-targeting therapies, potential mechanisms of resistance, and emerging predictive biomarkers.
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