Abstract A22: Preclinical evaluation of Bmi1 inhibition in pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of 6% and a rising mortality rate. The majority of patients present with advanced disease that is unresponsive to chemotherapy, highlighting the need for novel therapeutic strategies. Bmi1, a member of the Polycomb Group (PcG) family of transcriptional repressors, is known to be upregulated in PDA beginning in early pre-malignancy. Elevated Bmi1 expression in pancreatic tumors has been shown to correlate with poor prognosis, increased metastasis, and chemotherapy resistance in patients. Additionally, a recent study found Bmi1 to be required for pancreatic neoplasia in a murine model of PDA. Together, these data support the hypothesis that Bmi1 promotes the growth and survival of pancreatic tumors, suggesting it may be a novel therapeutic target. Bmi1 is a critical member of the PcG PRC1 complex, where it interacts with E3 ligase Ring1B in a dose-dependent manner to promote mono-ubiquitination of H2AK119, a histone modification that results in repression of gene expression. Among the best-characterized functions of Bmi1 is its negative regulation of the cdkn2a locus, which encodes two tumor suppressor proteins and cell cycle regulators, p16Ink4a and p14Arf. This is notable, as p16Ink4a is inactivated in most pancreatic tumors, often through epigenetic mechanisms. More recently, Bmi1 was found to have an additional role in G2/M checkpoint regulation following double strand breaks (DSBs). Knockdown of Bmi1 in breast and prostate cancer cell lines treated with etoposide to induce DSBs was found to induce G2/M arrest, while Bmi1 overexpression reduced G2/M arrest. This effect was mediated by reduced ATM activation. Based on these data, we decided to evaluate the effect of inhibiting Bmi1 both in cultured pancreatic tumor cells and in vivo using a genetically engineered mouse model of pancreatic ductal adenocarcinoma. PTC596 is an orally available, small-molecule inhibitor of Bmi1 developed by PTC Therapeutics that inhibits proliferation of human and murine PDA cell lines in vitro. Cell cycle analysis of PTC596-treated PDA cells supports G2/M arrest as a mechanism of inhibition. PTC596 is also well tolerated in vivo and can successfully be delivered to tumor tissues of treated mice. We are currently carrying out an intervention study in the KPC (K-rasLSL.G12D/+; p53LSL.R172H/+; Pdx1-Cre) genetically engineered mouse model of PDA to evaluate whether treatment with PTC596, alone or in combination with gemcitabine, confers a survival advantage or alters tumor growth kinetics. Preliminary results support slowed tumor growth and elevated levels of apoptosis in tumor tissues of treated mice. Ongoing work focuses on identifying the mechanism(s) of the observed effects on pancreatic tumors using tissues from mice treated with PTC596 as well as PDA cells with inducible knockdown of Bmi1. Citation Format: Jaime A. Eberle, Haoxuan Yuan, Carmine Palermo, Stephen A. Sastra, Liangxian Cao, Young-choon Moon, Melissa Dumble, Thomas Davis, Kenneth P. Olive. Preclinical evaluation of Bmi1 inhibition in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A22.