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.