VEGF and c-Met Blockade Amplify Angiogenesis Inhibition in Pancreatic Islet Cancer

Abstract

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.

In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer

“…MET is also expressed in endothelial cells and cooperates with VEGFRs in the induction and maintenance of the tumor vasculature (41). Overexpression of MET has been documented in papillary thyroid carcinoma and MTC (23)(24)(25) and, consistent with these studies, we found elevated MET expression in 53/63 PTC and 5/6 MTC tissue samples examined.…”

“…In preclinical studies, oral administration of cabozantinib resulted in rapid and robust tumor growth inhibition in multiple xenograft models, caused regression of tumor vasculature, inhibited tumor invasiveness and metastasis, and prolonged survival (39)(40)(41). The objective of this study was to evaluate the in vitro and in vivo antitumor efficacy of cabozantinib in a preclinical model of MTC.…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…3c,d). These results, taken together with the report linking HGF/cMet signalling in endothelial cells to tumour angiogenesis and growth [9][10][11] , led us to hypothesize that activation of Arf6 is a critical step in the HGF-dependent signalling pathway coupled to tumour angiogenesis. In support of this hypothesis, Arf6 was activated upon HGF stimulation of endothelial cells (Fig.…”

“…It has been reported that HGF/cMet signalling in endothelial cells is involved in tumour angiogenesis and growth [9][10][11] . In addition, it has been demonstrated that the mice lacking endothelial expression of the cMet-docking protein Gab1, which mediates HGF/cMet signalling, exhibit no apparent defects in developmental angiogenesis, but show impairment in postnatal angiogenesis after ischaemia 40 .…”

“…The hepatocyte growth factor (HGF)/cMet axis is a potent mitogenic, motogenic and morphogenic pathway 7,8 that can drive tumour angiogenesis and growth [9][10][11] . Expression of cMet and HGF is observed in the vast majority of solid tumours 12 .…”