tailieunhanh - Chapter 080. Cancer Cell Biology and Angiogenesis (Part 20)

The bevacizumab experience suggests that inhibition of the VEGF pathway will be most efficacious when combined with agents that directly target tumor cells. This also appears to be the case in the development of small-molecule inhibitors (SMI) that target VEGF receptor tyrosine kinase activity but are also inhibitory to other kinases that are expressed by tumor cells and important for their proliferation and survival. Sunitinib, FDA approved for the treatment of GIST (see above and Table 80-2), has activity directed against mutant c-Kit receptors, but also targets VEGFR and PDGFR, and has shown significant antitumor activity against metastatic RCC,. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 20 The bevacizumab experience suggests that inhibition of the VEGF pathway will be most efficacious when combined with agents that directly target tumor cells. This also appears to be the case in the development of small-molecule inhibitors SMI that target VEGF receptor tyrosine kinase activity but are also inhibitory to other kinases that are expressed by tumor cells and important for their proliferation and survival. Sunitinib FDA approved for the treatment of GIST see above and Table 80-2 has activity directed against mutant c-Kit receptors but also targets VEGFR and PDGFR and has shown significant antitumor activity against metastatic RCC presumably on the basis of its antiantiogenic activity. Similarly sorafenib originally developed as a Raf kinase inhibitor but with potent activity against VEGF and PDGF receptors increases progression-free survival in RCC. Thus agents that target both angiogenesis and tumor-specific signaling pathways may have greater efficacy against a broad range of cancers. A caveat is that RCC and GIST are highly dependent upon single signaling pathways VEGF and c-Kit respectively whereas most solid tumors use a panoply of interconnected proliferation and survival pathways that are redundant and likely to be less amenable to single-agent targeting. The success in targeting tumor angiogenesis has led to enhanced enthusiasm for the development of drugs that target other aspects of the angiogenic process some of these therapeutic approaches are outlined in Fig. 8011. Figure 80-11 Knowledge of the molecular events governing tumor angiogenesis has led to a number of therapeutic strategies to block tumor blood vessel formation. The successful therapeutic targeting of VEGF is described in the text. Other endothelial cell-specific receptor tyrosine kinase pathways . angiopoietin Tie2 and ephrin EPH are likely targets for the future. Ligation of the av03 integrin is required for EC .