Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met. Significance: This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis. Cancer Discovery; 2(3); 270–87. ©2012 AACR. Read the Commentary on this article by Lynn and Brekken, p. 211 This article is highlighted in the In This Issue feature, p. 193

We performed high-resolution atomic force microscopy indentation in live and snap-frozen fluorescently labeled mammary tissues to explore the origin of the tiss

Angiogenesis inhibitors that block VEGF 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 (RTK). 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 with 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 approximately 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. Cancer Res; 71(14); 4758–68. ©2011 AACR.

The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis Angiogenesis inhibitors;Endothelial cells;HGFR;Receptor tyrosine kinases;Signal transduction;Tumors;VEGF;VEGFR; Angiogenesis in tumors is driven by multiple growth factors that activate receptor tyrosine kinases. An important driving force of angiogenesis in solid tumors is signaling through vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Angiogenesis inhibitors that target this signaling pathway are now in widespread use for the treatment of cancer. However, when used alone, inhibitors of VEGF/VEGFR signaling do not destroy all blood vessels in tumors and do not slow the growth of most human cancers. VEGF/VEGFR signaling inhibitors are, therefore, used in combination with chemotherapeutic agents or radiation therapy. Additional targets for inhibiting angiogenesis would be useful for more efficacious treatment of cancer. One promising target is the signaling pathway of hepatocyte growth factor (HGF) and its receptor (HGFR, also known as c-Met), which plays important roles in angiogenesis and tumor growth. Inhibitors of this signaling pathway have been shown to inhibit angiogenesis in multiple in vitro and in vivo models. The HGF/c-Met signaling pathway is now recognized as a promising target in cancer by inhibiting angiogenesis, tumor growth, invasion, and metastasis.

The DLL/Notch signaling pathway plays an important role in cancer as a key driver in maintaining cancer stemness and inducing tumor angiogenesis. Many different types of DLL/Notch inhibitors have been developed and explored in clinical trials for cancer treatment, including small-molecule compounds to inhibit gamma-secretase and antibodies targeting Notch ligands or receptors. Despite promising efficacy of these inhibitors in preclinical studies, the overall clinical outcomes have been insufficient to advance to the next stage of clinical development primarily due to safety concerns or modest efficacy. To overcome the narrow therapeutic window of DLL/Notch inhibitors, diverse strategies for improving the balance between the safety and efficacy are currently being explored. Here, we review the clinical perspective and potential of DLL/Notch inhibitors as anticancer agents based on recent results from multiple clinical studies. An antibody specifically targeting Notch ligands or receptors may offer a better approach to reduce concerns about toxicity derived from broad-spectrum DLL/Notch blockers. In addition, combination therapy with an angiogenesis inhibitor targeting VEGF could be a better option for increasing anticancer efficacy. Taken together, the results of clinical trials suggest a bispecific antibody blocking the DLL/Notch and VEGF/VEGFR signaling pathways as a promising approach for effective anticancer treatment.