Targeting hyaluronan synthesis and signaling with BET inhibitors in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal reaction, which can promote tumor progression and contribute to chemo-resistance. The dense stroma can serve as a barrier to drug perfusion into the tumor by creating high intra-tumoral interstitial pressure. The dense stromal matrix in PDAC is caused by overproduction of extracellular matrix (ECM), mainly composed of collagens and hyaluronan. Hyaluronan is synthesized by HA synthase enzymes (HASs) and degraded by hyaluronidases (HYALs). Our previous work and other studies have shown that BRD4 protein, which is the most important member of bromodomain and extraterminal domain (BET) family proteins, is overexpressed in PDAC. BET proteins are “readers” of acetylated chromatin marks. Treatment with BET inhibitors also decreases tumor growth in PDAC mouse models. In this grant application, we propose our novel hypotheses that (1) BET protein inhibition decreases HA accumulation in PDAC tumors by decreasing the HA production. We further hypothesize that (2) BET inhibition will block receptor for HA-mediated motility (RHAMM)-driven oncogenic HA signaling. These hypotheses are based on strong preliminary data. We propose two specific aims. Aim 1: Investigate the role of BET proteins regulating HA levels in PDAC tumors and molecular mechanisms through which. Aim 2: Determine the ability of BET inhibitors to block HA signaling. This proposal includes innovative concept of HA regulation in PDAC, and has high biological and clinical relevance and significance, with potential for developing new therapeutic strategies for PDAC.