Editors' ChoiceCancer

Staying Alive: Specifically Targeting Tumor Vessels with Anti-Angiogenesis Therapy

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Science Translational Medicine  07 Mar 2012:
Vol. 4, Issue 124, pp. 124ec41
DOI: 10.1126/scitranslmed.3003952

For decades, it has been appreciated that most solid tumors usurp normal blood supply and generate new vessels (angiogenesis) to deliver oxygen and vital nutrients essential for continued tumor growth. Over the past decade, disrupting tumor angiogenesis has become a clinical reality with agents targeting vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) gaining approval for a number of different tumor types, including colon, lung, kidney, and brain. However, although these drugs have shown great promise, they induce substantial toxicity because the VEGF pathway plays a vital role in normal physiologic processes, including wound healing, menstruation, and ovulation.

Chaudhary and colleagues recently demonstrated that targeting tumor endothelial marker 8 (TEM8)—a cell-surface protein that is highly overexpressed in tumor blood vessels—has substantial therapeutic activity across a spectrum of experimental tumor types while preserving physiologic angiogenesis. The researchers developed a panel of monoclonal antibodies with specific activity against the TEM8 protein, then showed that the one with the highest potency, coined “L2,” was capable of significantly delaying growth in colorectal xenografts and mouse melanoma models as a monotherapy. Most importantly, mice being treated with L2 did not demonstrate signs of delayed wound healing or show any outward signs of toxicity to normal vasculature. The group was also able to show that mice lacking TEM8 gained no benefit from treatment with anti-TEM8 therapy, which suggests that the antibody was acting directly on TEM8. Encouragingly, the antibody to TEM8 was able to strongly potentiate the effects of several standard chemotherapeutic agents with widely disparate mechanisms of action when tested across a range of tumor types.

Although further work needs to be performed to fully elucidate the mechanism of action and generate a comprehensive efficacy and safety profile in nonrodent model systems, it appears that anti-TEM8 therapy may represent a new paradigm in targeted cancer therapies in which pathological but not physiological angiogenesis can be selectively disrupted.

A. Chaudhary et al., TEM8/ANTXR1 blockade inhibits pathologicalangiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21, 212–226 (2012). [Abstract]

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