Abstract 5065: Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 85% of pancreatic cancer and is one of the most lethal malignancies with limited therapeutic options. Chromatin-modulating small molecules, or epigenetic drugs, have the ability to reprogram cell fate and alter disease phenotypes. The potential of these drugs for PDAC therapy remains to be fully investigated. Screening a panel of epigenetic drugs identified MS275 (MS, also called entinostat), a histone deacetylase inhibitor, as capable of suppressing PDAC cell proliferation and inhibiting stromal fibrosis. Genome-wide expression analysis revealed that MS extensively reprograms the transcriptomes of tumor cells and cancer-associated fibroblasts (CAFs). In tumor cells, MS downregulates genes important for cell cycle progression inducing cytostasis. In CAFs, MS specifically represses the profibrotic transcription program responsive to TGF-beta, effectively inhibiting the fibrotic response. Consistent with this, MS blocks the activation of pancreatic stellate cells, the primary source for CAFs in PDAC, to repress the fibroblast-like phenotypes in these cells. Using an orthotopic transplantation model, we confirmed that MS treatment reduces tumor cell proliferation and decreases intratumoral fibrotic content. Importantly, we showed that MS substantially enhances chemocytotoxicity, synergizing with gemcitabine to reduce tumor burden in PDAC mouse models. Our study establishes a novel therapeutic strategy for PDAC based on epigenetic reprogramming induced by HDAC inhibition. Citation Format: Gaoyang Liang, Ruth Yu, Christopher Liddle, Morgan Truitt, Corina Antal, Annette Atkins, Ester Banayo, Michael Downes, Ronald Evans. Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5065. doi:10.1158/1538-7445.AM2017-5065