Jq1 Suppresses Tumor Growth In Tumorgraft Models Of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the most deadly of malignancies. Patients often present late in the course of disease limiting treatment options, with the majority of patients receiving chemotherapy. However, currently available chemotherapy has not impacted overall patient survival, and new therapies are urgently needed. Recently, our lab has documented that tumorgrafts derived specifically from primary PDAC tumors retain characteristics of the tumors of origin. In terms of drug evaluation, tumorgraft models have been shown to be predictive of clinical utility because these models retain tumor heterogeneity, recapitulate tumor architecture, and contain human stroma. To date, most efforts to use tumorgraft models to identify effective agents for the treatment of PDAC have taken an “all comers approach”; but this approach has thus far identified no effective therapies. We proposed that JQ1, a compound that targets the oncogene c-Myc, would be efficacious for the treatment of PDAC, based on molecular characteristics of these tumors. The oncogene c-Myc is amplified or overexpressed in a 30-45% of primary or metastatic PDAC tumors. Also, overexpression of this oncogene is sufficient to induce tumor formation in a genetically engineered mouse model of PDAC, suggesting a critical role in the tumorigenesis of this tumor type. JQ1 is a novel compound in that it is a relatively specific bromodomain inhibitor. Bromodomain containing proteins recognize acetylated lysine residues on histones and direct the assembly of macromolecular molecules to the chromatin for transcription. A specific subfamily of these proteins, known as BETs (bromodomain and extra-terminal), recruit c-Myc to specific sites for transcription. Exposure of PDAC cells to JQ1 decreases the expression and therefore the activity of c-Myc. To test the effectiveness of JQ1 in vivo, we administered 50 mg/kg of JQ1 i.p. once a day for 28 days and monitored tumor growth in a panel of 5 PDAC tumorgraft models. This dose and schedule of JQ1 administration was well tolerated in mice with no significant toxicity. Our data indicate that JQ1 suppressed tumor growth in all 5 models, compared to vehicle control treated mice. The data also showed a modest, JQ1-induced down regulation of c-Myc and NFkB. We conclude that JQ1 and other bromodomain inhibitors warrant further investigation as potentially effective agents for the treatment of PDAC. This work was supported by UAB/UMN SPORE in pancreatic cancer (P50 CA101955). Citation Format: Patrick L. Garcia, Tracy Gamblin, Leona N. Council, John D. Christein, J. Pablo Arnoletti, Martin J. Heslin, Joseph H. Richardson, Jun Qi, Jay E. Bradner, Karina J. Yoon. JQ1 suppresses tumor growth in tumorgraft models of pancreatic ductal adenocarcinoma. [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 4612. doi:10.1158/1538-7445.AM2014-4612