Novel VEGF-independent strategies targeting tumor vasculature: clinical aspects

In the last decades, the active research in the field of tumor angiogenesis has led to the development of a class of agents providing an effective inhibition of neo-vessel formation through the blockade of VEGF related pathways. More recently, the identification of other factors involved in tumor angiogenesis, such as platelet-derived growth factor, fibroblast growth factor and Angiopoietins has emphasized the need to develop agents targeting multiple pro-angiogenic pathways. Although contrasting data are currently available regarding the clinical efficacy of multikinase inhibitors, Sunitinib, Sorafenib and Pazopanib have displayed encouraging results, and have fuelled further evaluations. Moreover, definitive data are also eagerly awaited regarding the clinical role of angiopoietins inhibitors. On the other hand, the existence of morphological, functional and architectural differences between normal and tumor vasculature has provided solid basis for the development of a novel class of compounds, known as Vascular Disrupting Agents (VDAs) able to selectively disrupt existing tumor vessels. After initial concerns related to the potential development of severe cardiovascular toxicities, further clinical investigations have shown a safe toxicity profile for these agents. Moreover, despite the discouraging data on dolostatin-10 and ASA404, several VDAs, including CAP4, Ombrabulin and Pinabulin have already shown promising activity in phase I-II clinical trials warranting more advanced evaluations. In this review we aimed at summarizing the most relevant VEGF-independent strategies targeting tumor vasculature, focusing on the clinical development of novel antiangiogenic agents including multikinase and angiopoietins inhibitors as well as VDAs.