Abstract 377: Inhibition of c-Met and VEGFR by XL184 reduces tumor invasiveness and metastasis and prolongs survival of RIP-Tag2 transgenic mice

Abstract

Abstract Recent studies have shown that inhibition of VEGF signaling can promote tumor invasiveness and metastasis in some preclinical models. The mechanism underlying the increased aggressiveness is not fully understood but activation of the hepatocyte growth factor/c-Met pathway may be a factor. We addressed this mechanism by determining whether inhibition of VEGFR and c-Met together can reduce tumor growth and invasiveness and improve host survival. Our approach was to compare the effects of a tyrosine kinase inhibitor, XL184 (BMS-907351), which blocks VEGFR and c-Met, with the effects of an antibody that selectively blocks mouse VEGF. After treatment of pancreatic islet cell tumors in 14-week-old RIP-Tag2 mice withanti-mouse VEGF antibody for 3 weeks, the tumors were smaller (tumor area 4.3 ± 0.8 mm2 in antibody group versus 17.3 ± 6.5 mm2 in vehicle group, P < 0.05) but had greater expression of c-Met. Tumors treated with anti-VEGF antibody also had more irregular borders, indicative of invasion of the surrounding acinar pancreas (invasion index 18.9 versus 12.7 in vehicle group, P < 0.05), and more abundant liver metastases (metastases 2.73 ± 1.83 /mm2 versus 0.45 ± 0.12 /mm2 in vehicle group, P < 0.05). By comparison, mice treated with XL184 not only had smaller tumors (tumor area 0.7 ± 0.1 mm2, P < 0.05) than in the other groups but also had less invasive tumors (invasion index 4.5, P < 0.05), and lacked liver metastases. All mice treated with XL184 from 14 weeks of age survived until 20 weeks (n = 6), but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that end point. These results show that selective inactivation of VEGF reduces tumor growth but leads to greater invasiveness and metastasis in the RIP-Tag2 model. However, inhibition of VEGFR and c-Met by XL184 not only slows tumor growth but also decreases tumor invasiveness and liver metastasis and prolongs host survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 377.