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. 80- 11. Figure 80-11 Knowledge of the molecular events governing tumor angiogenesis has led to a number of therap eutic 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 (e.g., angiopoietin/Tie2 and ephrin/EPH) are likely targets for the future. Ligation of the α v β 3 integrin is required for EC survival. Integrins are also required for EC migration and are important regulators of matrix metalloproteinase (MMP) activity, which modulates EC movement through the ECM as well as release of bound growth factors. Targeting of integrins includes development of blocking antibodies, small peptide inhibitors of integrin signaling, and arg-gly-asp- containing peptides that prevent integrin:ECM binding. Peptides derived from normal proteins by protea lytic cleavage, including endostatin and tumstatin, inhibit angiogenesis by mechanisms that include interfering with integrin function. Signal transduction pathways that are dysregulated in tumor cells indirectly regulate EC function. Inhibition of EGF-fam ily receptors, whose signaling activity is upregulated in a number of human cancers (e.g., breast, colon, and lung cancers), results in downregulation of VEGF and IL- 8, while increasing expression of the antiangiogenic protein thrombospondin-1. The Ras/MAP K, PI3K/Akt, and Src kinase pathways constitute important anti- tumor targets that also regulate the proliferation and survival of tumor- derived EC. The discovery that EC from normal tissues express tissue- specific "vascular addressins" on their cell surface suggests that targeting specific EC subsets may be possible. Further Readings Bild AH et al: Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353, 2006 [PMID: 16273092] Dai Y, Grant S: Targeting multiple arm s of the apoptotic regulatory machinery. Cancer Res 67:2908, 2007 [PMID: 17409392] Ferrara N, Kerbel RS: Angiogenesis as a therapeutic target. Nature 438:967, 2005 [PMID: 16355214] Finkel T et al: The common biology of cancer and ageing. Nature 448:767 , 2007 [PMID: 17700693] Huber MA et al: Molecular requirements for epithelial- mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548, 2005 [PMID: 16098727] Kaelin Jr WG: The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:686, 2005 Panares RL, Garcia AA: Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther 7:434, 2007 Sharma SV et al: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169, 2007 [PMID: 17318210] Sherbenou DW, Drucker BJ: Applying the discovery of the Philadelphia chromosome. J Clin Invest 117:2068, 2007 Vousden KH, Lane DP: p53 in health and disease. Nat Rev Mol Cell Biol 8:275, 2007 [PMID: 17380161] Bibliography Jones PA, Ba ylin SB: The epigenomics of cancer. Cell 128:683, 2007 [PMID: 17320506] Michaloglou C et al: BRAF E600 -associataed senescence- like cell cycle arrest of human naevi. Nature 436:720, 2005 [PMID: 16079850] Soda M et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561, 2007 [PMID: 17625570] Willet CG et al: Direct evidence that VEGF- specifi antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145, 2004 . Chapter 080. Cancer Cell Biology and Angiogenesis (Part 20) The bevacizumab experience suggests that inhibition of the VEGF. 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. tumor cells indirectly regulate EC function. Inhibition of EGF-fam ily receptors, whose signaling activity is upregulated in a number of human cancers (e.g., breast, colon, and lung cancers),