Abstract A107: In vivo screen of regorafenib in a panel of low passage START-PDX colorectal models: Working to identify a sensitive patient subpopulation.

Abstract

Abstract Background: Regorafenib is a multi-tyrosine kinase recently approved for unresectable and drug refractory gastrointestinal stromal tumors (GIST) and treatment-refractory colorectal cancers regardless of Ras status. While a subset of colorectal cancer patients have reported benefit from regorafenib therapy, the majority does not benefit and attempts to identify a subpopulation of sensitive colorectal patients have not been successful. To better understand which colorectal cancer patients may respond to regorafenib we screened a panel of low passage colorectal models from the START patient-derived xenograft (PDX) platform and compared results to model characteristics. Methods: PDX colorectal models were established in athymic nude mice from primary or metastatic patient tissue or fluid and once established were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model DNA was extracted and subjected to mutation profiling and growth factor receptor expression was interrogated using immunohistochemistry. Drug sensitivity studies were performed evaluating regorafenib at 25-30 mg/kg once daily for at least twenty-one days. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion. Results: To date forty colorectal START-PDX models have been screened against regorafenib. Three models (ST201, ST238 and ST800) reported tumor regressions or partial responses even with activating K-Ras or B-Raf mutations present. An additional 30% of evaluated models reported tumor stasis (T/C= 0-10%) and remaining models demonstrated varying degrees of sensitivity or resistance to regorafenib. High expression of EGFR was reported in two of the most sensitive models and was reduced in the models resistant to regorafenib. Conclusion: We have screened preclinical activity of regorafenib towards a panel of colorectal 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 sensitive patient subpopulation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A107. Citation Format: Michael J. Wick, Lizette Gamez, Armando Diaz, Teresa L. Vaught, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Lon Smith, Ron Drengler, Kyriakos P. Papadopoulos. In vivo screen of regorafenib in a panel of low passage START-PDX colorectal models: Working to identify a sensitive patient subpopulation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A107.