Abstract C171: Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC).

Abstract

Abstract Background: BTC represents the second most common primary cancer of the hepatobiliary system and is associated with a poor prognosis. Activation of PI3K/mTOR and hedgehog pathways has been demonstrated in biliary cancer. Activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenesis through S6K1-mediated Gli phosphorylation. Recently, synergistic antitumor efficacy was demonstrated with the combination of hedgehog and mTOR inhibitors, particularly in cases with mTOR/S6K pathway in esophageal cancer (Cancer Cell 2012; 21(3):374-87). Methods: Gene expression profiling was performed on 10 human biliary tract cancer cell lines (MMNK-1, Mz-ChA-1, Sk-ChA-1, KKU-M213, KKU-M214, KKU-M055, KKU-M139, M213L5H, and M213LOH) by real-time qRT-PCR. CellTiter-Glo® luminescent cell viability assay, colony formation, and stem cells morphology spheres were conducted to examine the effects of the combination of Rapamycin and Vismodegib on cell proliferation. Western-blot assay was used to examine the related protein expression. Fluorescence-activated cell sorting (FACS) was used to examine the effects of the combination on BTC stem cells. Results: Based on Gli1 and S6K gene expression, the Mz-ChA-1 and Sk-ChA-1 cell lines were chosen to investigate the effects of the combination of Rapamycin and Vismodegib on BTC (Table 1). Combination of Rapamycin and Vismodegib exhibited the synergistic antiproliferative effect on Mz-ChA-1 cells. The combination of Rapamycin and Vismodegib inhibited the Mz-ChA-1 cell proliferation, colony formation and stem cell sphere formation. This combination therapy decreases the NANOG, OTC3/4, and E-Cadherin gene expression in Mz-ChA-1 stem cells. Furthermore, the drug combination can decrease the phospho-p70S6K and Gli1 protein and increase cleaved caspase-3 expression in Mz-ChA-1 cells. No such effect was observed in Sk-ChA-1 cells.Conclusions: Crosstalk between the mTOR pathway and HH pathway provides a new avenue for combination therapy in BTC with hedgehog and mTOR inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C171. Citation Format: Mingxin Zuo, Asif Rashid, Chaitanya Churi, Mien-Chie Hung, Milind Javle. Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC). [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 C171.