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.
The proposed research is relevant to public health because the current proposal seeks to target the enzymes and receptor involved in hyaluronan synthesis and hyaluronan-mediated signaling in pancreatic cancer is ultimately expected to help identify novel therapeutic strategies to overcome the chemo-resistance in this highly lethal malignancy. Thus, the proposed research is relevant to the mission of the NIH that pertains to improving the health of the Nation by supporting research in the cure/treatment of human disease.
| Ebine, Kazumi; Kumar, Krishan; Pham, Thao N et al. (2018) Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells. Sci Rep 8:13225 |
