Abstract 2603: Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models

Abstract

Abstract The efficacy and tolerability of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 combination were explored in pancreatic and biliary tract preclinical tumor xenograft models. These studies were based on the hypotheses that combination efficacy may occur by several possible mechanisms including inhibition of DNA repair or increase of hypoxia by Pimasertib, or by differential targeting of the oxic and hypoxic tumor compartments by Pimasertib and TH-302 respectively. Since Pimasertib and TH-302 had each been tested in separate clinical trials in pancreatic cancer with gemcitabine (NCT01016483 and NCT01144455 respectively), these data could provide the rationale for clinical testing of this novel combination in pancreatic cancer. The combination was also tested in biliary tract cancer models (cholangiocarcinoma and gall bladder) based on the reported sensitivity of these tumor types to MEK inhibitors, their hypoxic nature, and the prevalence and high unmet need of these indications, particularly in Asia. The results showed that in the MIA PaCa-2 human pancreatic xenograft model, combination efficacy was observed and found to be schedule dependent. The greatest combination efficacy occurred when Pimasertib was administered first, 2 hours prior to TH-302, suggesting a unique combination mechanism in cells when the MAPK signaling pathway is suppressed first. The combination was subsequently explored in 2 additional pancreatic models and a panel of biliary tract patient-derived xenograft (PDX) models. In 10 cholangiocarcinoma PDX models tested, 3 models were responders to Pimasertib monotherapy and 4 models converted from being a non-responder with either monotherapy to a responder with the Pimasertib TH-302 combination using the%TV (tumor volume) criteria, which is related to a clinical PR RECIST response. Combination effects were not observed in 2 additional pancreatic or 6 gall bladder models tested. Some models were highly sensitive to Pimasertib or TH-302 monotherapy, making combination effects difficult to observe. Biomarker analyses are ongoing to identify markers that could predict which tumors are the most sensitive to this combination therapy. Citation Format: Jianguo Ma, Sakeena Syed, Lindsey Crowley, Jamie Shaw, Janet Ogden, Brian Elenbaas, Samantha Goodstal. Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2603. doi:10.1158/1538-7445.AM2015-2603