Abstract 1378: Preclinical efficacy of the triple VEGFR inhibitor tivozanib (AV-951) in chimeric breast and lung tumor models

Abstract

Abstract All solid tumors are thought to require neo-vascularization. Therefore pharmacologic inhibition of angiogenesis may represent an important component for treating many therapeutically challenging tumor types. 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 in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition. To test preclinical efficacy of tivozanib in other cancer types, we chose primary mouse tumor models due to their ability to capture the complex heterotypic interactions between tumor cells and the microenvironments. Our mouse tumor model strategy involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera formation to enable direct tumor induction in tissues containing both normal and engineered cells. A HER2 driven breast model as well as an allelic series of lung cancer models containing EGFR, KRAS, or HER2 oncogenes demonstrated that resultant adenocarcinomas arose within surrounding normal tissue and exhibited features of advanced malignancies. In this study, we tested the response of HER2 driven breast tumors as well as KRAS and EGFR driven lung tumors to the VEGFR inhibitor tivozanib in tumor bearing chimeric mice. We observed that although tivozanib treatment conferred significant survival benefit to the tumor bearing mice in all three models, it is not able to eradicate all tumor cells. Response to tivozanib in the breast model is much more heterogeneous than in the lung models, with some tumors exhibiting significant regression while others showing progression on treatment, either initially or after a period of response. In contrast, lung tumors showed more uniform response to tivozanib treatment initially, but tumors quickly grew back upon discontinuation of tivozanib treatment. These results indicate that both breast and lung cancer patients could potentially benefit from sustained anti-angiogenesis therapy, and combination of anti-angiogenesis with tumor targeting agents may be required for enduring efficacy. 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 1378.