Resisting Arrest

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Science  18 Nov 2005:
Vol. 310, Issue 5751, pp. 1091
DOI: 10.1126/science.310.5751.1091a

An exciting class of cancer drugs acts by disrupting the growth of new blood vessels that supply solid tumors with oxygen and other essential nutrients. Because antiangiogenic therapies target genetically stable endothelial cells rather than genetically adaptable tumor cells, it had been hypothesized that tumors would be unlikely to develop resistance to these drugs. However, the results of clinical trials reveal that tumors do in fact eventually escape the growth-inhibitory effects of these drugs, although the underlying mechanisms of resistance have been unclear.

Casanovas et al. show that resistance can arise when tumors exploit a redundancy in the signaling pathways that drive angiogenesis; that is, when a drug incapacitates one pathway, tumors are able to reactivate angiogenesis through a second pathway. In a mouse model of pancreatic cancer, blocking vascular endothelial growth factor (VEGF) signaling with an antibody to VEGF receptor 2 (VEGFR2) produced a temporary arrest of tumor angiogenesis and tumor growth. Subsequently, a second wave of angiogenesis, driven by fibroblast growth factors (FGFs), led to resumption of tumor growth. Inhibiting FGF signaling during this second stage effectively blunted tumor recovery from hypoxia, and the authors propose that maximal therapeutic benefit may come from the use of drug combinations that target multiple angiogenic pathways. — PAK

Cancer Cell 8, 299 (2005).

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