Angiogenesis Inhibition: State of the Art, Forgotten Strategies and New Perspectives in Cancer Therapy

Roberto      Benelli; Nicoletta      Ferrari

Abstract

In 1971, J. Folkman started his crusade on the therapeutic targeting of tumor angiogenesis [1]. This strategy gained an increasing number of sustainers showing promising, if not sensational results in animal models. Numerous potential targets were identified on the endothelial cell, causing the sensation to have no more secrets to disclose. Times were mature for an optimistic clinical transfer. This transfer immediately appeared a disaster: most molecules showed high toxicities, without appreciable therapeutic effects. Several trials were suddenly discontinued by the pharmaceutical industry, was it the end of “antiangiogenesis”? Fortunately, among numerous endothelial targets, one survived as potentially interesting: vascular endothelial growth factor (VEGF) and its receptor. Today we know that bevacizumab, a humanized anti VEGF antibody, significantly improves patients life expectancy, when associated to the chemotherapy of colon and other solid cancers. In addition synthetic inhibitors of tyrosine kinase receptors (TKR) - like sunitinib and sorafenib- are deeply investigated. While these molecules have “saved” the anti angiogenic theory and will be perfected, we could ask why so many promising drugs failed in clinic. Among several answers, one can resume the others: the milestones of the anti-angiogenic theory were misunderstood by its clinical application. Born for chemoprevention, angiogenesis was targeted in advanced cancers, frequently as monotherapy. This implied the study of a MTD in phase I trials causing severe side effects, while an “optimal dose for chronic scheduling” (ODCS) should be tested instead. The evaluation of rapidly evolving cancers with an already established vascularization was a clear limit to those anti-angiogenic molecules unable to affect a completed angiogenic process. In addition it was immediately clear that classic response evaluation protocols were inadequate for anti-angiogenic assessment, due to the short time of the screening, and the lack of surrogate markers. In this review we revisit the different therapeutic strategies historically developed to target tumor vessels, describe the state of the art for VEGF and TKR inhibitors, comment recent trials based on molecules with known anti angiogenic activities and finally suggest possible guidelines for improving basic research and clinic experimentation.

Keywords: Angiogenesis, endothelial cell, vessel, VEGF, therapy, clinical trial

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