Abstract A13: Reduction of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184

Abstract

Abstract Inhibition of vascular endothelial growth factor receptor (VEGFR) signaling can slow tumor growth and prolong host survival but can also promote invasiveness and metastasis in some preclinical models. Although the mechanisms involved are unclear, hypoxia-induced activation of pro-invasive pathways involving hepatocyte growth factor and its receptor c-Met may be a factor. We sought to address this mechanism by determining whether inhibition of VEGFR together with c-Met can reduce tumor invasiveness and improve host survival as well as reduce tumor growth. Our approach was to compare the effects of a tyrosine kinase inhibitor, XL184, that blocks VEGFR and c-Met with the effects of an antibody that selectively blocks mouse VEGF in 14-week-old RIP-Tag2 transgenic mice, a model of pancreatic neuroendocrine carcinoma. In this model, tumors arise from pancreatic islet beta cells in their natural microenvironment, and the effects of inhibitors can be tested at multiple stages of tumorigenesis. After treatment with anti-mouse VEGF antibody for 3 weeks, the tumors were smaller than vehicle-treated tumors (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 and had more irregular borders. After the anti-VEGF antibody, irregularity of the tumor perimeter indicative of invasion of the surrounding acinar pancreas was increased (invasion index 18.9 versus 12.7 in vehicle group; P < 0.05), and liver metastases were more numerous (metastases 2.73 ± 1.83 /mm2 versus 0.45 ± 0.12 /mm2 in vehicle group; P < 0.05). By comparison, tumors treated with XL184 not only were smaller (tumor area 0.7 ± 0.1 mm2; P < 0.05) than in the vehicle or anti-VEGF antibody group but also were less invasive (invasion index 4.5; P < 0.05) and had no liver metastases. All mice treated from 14 weeks of age with XL184 (n = 6) survived until 20 weeks, 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 together with c-Met not only slows tumor growth but also decreases tumor invasiveness and liver metastases and prolongs host survival. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A13.