Antiangiogenesis beyond VEGF inhibition: A journey from antiangiogenic single-target to broad-spectrum agents

Although the inhibition of angiogenesis is an established modality of cancer treatment, concerns regarding toxicity and drug resistance still constitute barriers to be overcome. For almost a decade since the approval of bevacizumab in 2004, the efforts on antiangiogenic therapeutics have been mainly focused in inhibiting the VEGF pathway. The ongoing understanding of the complexity of the angiogenic process has broadened the spotlight to include concurrent and downstream players to the list of targeted inhibitors. In this review, we summarize the currently existing and the promising antiangiogenic treatments, envisioning an apparent evolutionary trend towards the development of angiogenesis inhibitors of three modalities: single-target, multi-target, and broad-spectrum agents. The clinical efficacy and some structural aspects of monoclonal antibodies, small molecules, endogenous and synthetic angiogenesis inhibitors and their molecular targets are discussed, and the targeting of endothelial cells with the use of cytotoxic drugs in a metronomic schedule is appraised. The reader is invited to revisit current expectations about antiangiogenic therapy in an attempt to set consistent clinical endpoints from which patients could gain real and lasting clinical benefits.