Targeting tumor angiogenesis

Four decades after the seminal work of Judah Folkman, in 1971, cancer therapies based on the suppression of neo-angiogenesis (Folkman, N Engl J Med 285:1182-1186, 1971) are becoming a reality (Verheul et al., Clin Cancer Res 14(11):3589-3597, 2008). The shift toward the up-regulation of pro-angiogenic factors secretion from both tumor and stroma, results from the interplay between endothelial cell activation, proliferation, extracellular matrix degradation, migration, canalization. It leads to the generation of a chaotic vascular vessels network in prostate cancer tissue (Ahmed and Bicknell, Method Mol Biol 467:3-24, 2009), which can be detected also by modern imaging techniques based on magnetic resonance, ultrasound, and nuclear imaging through targeting of key angiogenic factors (Russo et al., BJU Int 110(11 Pt C):E794-E808, 2012). This hopefully will lead to further improvements in prostate cancer diagnosis and staging. Preclinical evidence indicates that angiogenesis inhibitors can improve the efficacy of conventional cytotoxic agents mainly by normalizing tumor blood flow, thus improving drug delivery. Although significant biological activity of most vascular growth factors-interfering agents is demonstrated in preclinical models, single-agent activity is almost universally poor (Aragon-Ching et al., J Oncol 2010:361836, 2010). Due to the redundancy within the signalling pathways that promote angiogenesis, combining anti-angiogenic agents with different mechanisms of action seems likely to significatively potentiate their therapeutic efficacy (Corcoran and Gleave 2012; Ellis and Hicklin, Nat Rev Cancer 8:579-591, 2008; Verheul et al., Cancer Chemother Pharmacol 60:29-39, 2007).