Abstract 1293: JQ1 sensitivity of patient-derived xenograft models of cholangiocarcinoma

Abstract

Abstract Cholangiocarcinoma (CCA) is a lethal malignancy arising from cholangiocytes in any part of the biliary tree. The incidence of CCA has been on the rise worldwide, and the prognosis and clinical outcome have remained essentially unchanged for 30 years. The majority of patients are diagnosed at late stage, and surgery continues to be the only cure. Patients receive systemic chemotherapy with the first-line combination therapy comprising gemcitabine and cisplatin. Median survival for these patients is <12 months, emphasizing the need to improve current treatment. A step toward improving outcome is the pre-clinical evaluation of novel therapeutics. Recently the bromodomain and extra-terminal domain (BET) inhibitor JQ1 has been shown to suppress tumor growth in preclinical models of multiple tumor types. The therapeutic effect of JQ1 has been attributed, at least in part, to its ability to inhibit c-Myc expression. 95% of CCA tumors express c-Myc and its down-regulation has been shown to reduce the invasive potential of CCA cells, suggesting that c-Myc contributes to CCA phenotype. Our lab recently evaluated the efficacy of the BET inhibitor JQ1 in CCA patient-derived xenograft mouse models. JQ1 suppressed CCA tumor growth in 2 of the 3 models. To determine gene products whose upregulation or downregulation is responsible for the differences in sensitivity to JQ1 among our CCA models, we generated expression profiles of tumors from vehicle control and JQ1 treated mice using NanoString technology (nCounter PanCancer Pathways panel). Our data demonstrate that JQ1 inhibited the expression of c-Myc to a greater extent in the sensitive models than in the insensitive model. Expression array data showed further that gene products involved in cell cycle and DNA repair pathways were also decreased by JQ1. Of particular interest were two transcriptional targets of c-Myc, Chk1 and BRCA2, each of which is involved in DNA damage response. Immunohistochemistry staining confirmed expression profile analyses. We conclude that the inhibition of cell cycle and DNA repair genes may contribute to the mechanism of action of JQ1 in CCA tumors. Citation Format: Aubrey L. Miller, Patrick L. Garcia, Tracy L. Gamblin, Leona N. Council, Xiangqin Cui, James E. Bradner, Eddy S. Yang, Karina J. Yoon. JQ1 sensitivity of patient-derived xenograft models of cholangiocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1293.