Abstract B031: Targeting epigenetic machinery to revoke stromal pro-tumorigenicity and enhance efficacy in pancreatic cancer therapy

Abstract

Abstract Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) induce prominent desmoplasia in part by activating fibroblasts or their progenitors in the stroma. The resultant cancer-associated fibroblasts (CAFs) often switch on the pro-desmoplastic, pro-inflammatory and/or pro-tumorigenic transcriptional programs, contributing to tumor progression and therapeutic resistance. Identifying and targeting epigenetic machinery essential for stromal fibroblast activation provides potential strategies to revoke stromal pro-tumorigenicity and overcome therapeutic resistance in PDAC. Here we identify Class I histone deacetylases (HDACs) as key epigenetic regulators facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in stromal fibroblasts. Mechanistically, HDACs coordinate the establishment of chromatin architecture that enables the activation of pro-desmoplastic programs directed by the transcriptional factor axis of serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also facilitate the induction of pro-inflammatory program in stromal fibroblasts, supporting leukemia inhibitory factor (LIF)-mediated pro-tumorigenic crosstalk. Both HDAC depletion in CAFs and treatment of the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a novel lipogenic fibroblast subpopulation in CAFs, a potential precursor population for activated myofibroblasts in vivo. Our work pinpoints a critical role of HDACs in driving stromal pro-tumorigenicity and highlights the stromal targeting capacity of HDACi therapy. Furthermore, the clinical utility of HDACi therapy is often hindered by limited potency and nonnegligible systemic toxicity of the HDAC inhibitors. To facilitate the translation of HDACi-based therapy, we develop a polymer-based bottlebrush pro-drug (BPD) nanoparticle incorporating Ent. The Ent-BPD nanoparticle overcomes the limitations of conventional HDACi therapy by sustaining long-lasting release of HDACi activity specifically at the tumor sites. Administration of Ent-BPD in PDAC mouse models achieves superior intratumoral HDACi potency and enhanced therapeutic efficacy compared to the free drug Ent treatment; meanwhile, it avoids the systemic toxicity associated with the free drug treatment. Our work further demonstrates a promising strategy for the clinical adaptation of HDACi-based therapy. Citation Format: Gaoyang Liang, Jeremiah A. Johnson, Ronald M. Evans. Targeting epigenetic machinery to revoke stromal pro-tumorigenicity and enhance efficacy in pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B031.