Abstract A22: Response to the triple VEGFR inhibitor tivozanib (AV-951) in KRAS and EGFR driven lung tumors developed in chimeric mouse models

Abstract

Abstract Lung cancer is one of the most prevalent and deadly malignancies in the world, with more than 213,000 new cases diagnosed each year in the US and a five year survival rate of 15%. Activating mutations in a number of key signaling genes including KRAS, EGFR, and HER2 have been identified. Mutations in EGFR are highly correlated with sensitivity to small molecule EGFR inhibitors, although resistance tends to develop within a short period of time after initiation of treatment. Targeted inhibition of KRAS has not been successful so far, which in turn fueled efforts to identify tractable alternative therapeutic points of intervention. Because all solid tumors are thought to require neo-vascularization, pharmacologic angiogenesis inhibition may represent an attractive therapeutic strategy for these challenging tumor settings. One attractive anti-angiogenesis agent is the ATP competitive small molecule VEGFR inhibitor tivozanib (AV-951). tivozanib exhibits picomolar inhibitory activity against all three VEGF receptors, a multi-day T1/2 in humans, and demonstrates robust clinical activity demonstrated in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition. In an effort to recapitulate the stochastic nature of human cancer in genetically engineered mouse models and to maximize their use in preclinical settings, we developed a mouse tumor model strategy involving stepwise genetic manipulation of embryonic stem (ES) cells and chimera formation to enable direct tumor induction in tissues containing both normal and engineered cells. An allelic series of lung cancer models containing EGFR, KRAS, or HER2 oncogenes demonstrated that resultant adenocarcinomas arising within normal lung tissue exhibited features of advanced malignancies. In this study, we tested the response of KRAS and EGFR driven lung tumors to the VEGFR inhibitor tivozanib in tumor bearing chimeric mice identified by bioluminescent imaging. We demonstrated that tivozanib treatment conferred significant survival benefit to the tumor bearing mice. Consistent with previous reports that tumors become more dependent on neo-angiogenesis for survival and proliferation, we observed sensitivity to tivozanib in advanced adenocarcinomas but not hyperplasia or small adenomas. In addition, we found that upon discontinuation of tivozanib treatment, tumors quickly grew back and became less sensitive to further tivozanib treatment. These results indicate that lung cancer patients could potential benefit from anti-angiogenesis therapy, but sustained inhibition of all VEGF receptors may be important to prevent development of resistance. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A22.