Abstract 2985: In vivo evaluation of regorafenib and liposomal-doxorubicin in a panel of low passage uterine START-PDX tumor models

Abstract

Abstract Background: Uterine and ovary cancers account for a majority of gynecologic cancer-related deaths in Western countries. While initial cure rates are high, recurrent disease is often chemoresistant with few treatment options. Regorafenib is a recently approved multi-tyrosine kinase targeting VEGFR2 and Tie2. As Tie2 has been implicated in the pathogenesis of uterine cancers, we evaluated regorafenib as a potential therapy in our panel of uterine PDX models and compared activity to the approved therapy liposomal-doxorubicin. Methods: PDX uterine models were established in immune-deficient mice from primary or metastatic patient tissue and once established were confirmed by histologic comparative analysis with patient tumor tissue, linked with patient treatment and outcome data and characterized for activating mutations and known amplifications. Drug sensitivity studies were performed in each model evaluating daily oral regorafenib or weekly intravenous liposomal-doxorubicin versus control; group sizes were n=2-3 for control and n=1 for treatment arms. Study endpoints included a set day following treatment initiation with tumor growth inhibition or delay and regression reported at study completion. Results: For this project we evaluated twenty-five uterine models. Statistically significant (p<0.05) regorafenib activity was reported in a subset of evaluated endometrial models; however, activity was not limited to a particular tumor subtype or mutation profile. Liposomal-doxorubicin also demonstrated differential but significant tumor growth inhibition towards models in the evaluated panel. Conclusion: We have screened preclinical activity of regorafenib and liposomal-doxorubicin towards a panel of uterine START-PDX models and identified sensitive and resistant models. Additional genomic and characterization studies are underway to better understand activity of regorafenib with the goal of identifying a sensitivity profile for patient stratification. Citation Format: Justin Meade, Michael J. Wick, Teresa Vaught, Lizette Gamez, Roger Chavez, Anthony Tolcher, Drew Rasco, Amita Patnaik, Allan J. White, Kyriakos Papadopoulos. In vivo evaluation of regorafenib and liposomal-doxorubicin in a panel of low passage uterine START-PDX tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2985. doi:10.1158/1538-7445.AM2014-2985