Inhibition of angiopoietin-2 (Ang2) can slow tumor growth, but the underlying mechanism is not fully understood. Because Ang2 is expressed in growing blood vessels and promotes angiogenesis driven by vascular endothelial growth factor (VEGF), we asked whether the antitumor effect of Ang2 inhibition results from reduced sprouting angiogenesis and whether the effect is augmented by inhibition of VEGF from tumor cells. Using Colo205 human colon carcinomas in nude mice as a model, we found that selective inhibition of Ang2 by the peptide-Fc fusion protein L1-7(N) reduced the number of vascular sprouts by 46% and tumor growth by 62% over 26 days. Strikingly, when the Ang2 inhibitor was combined with a function-blocking anti-VEGF antibody, the number of sprouts was reduced by 82%, tumor vascularity was reduced by 67%, and tumor growth slowed by 91% compared with controls. The reduction in tumor growth was accompanied by decreased cell proliferation and increased apoptosis. We conclude that inhibition of Ang2 slows tumor growth by limiting the expansion of the tumor vasculature by sprouting angiogenesis, in a manner that is complemented by concurrent inhibition of VEGF and leads to reduced proliferation and increased apoptosis of tumor cells. Cancer Res; 70(6); 2213-23. ©2010 AACR.

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Angiogenesis inhibitors that block vascular endothelial growth factor receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTKs). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small molecule inhibitors that potently block multiple RTKs including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 to those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated ~ 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.