Targeting hyaluronan synthesis and signaling with BET inhibitors in pancreatic cancer

胰腺导管腺癌(PDAC)以密集的间质反应为特征，可 促进肿瘤进展，并导致化疗耐药。致密的基质可以作为 通过在肿瘤内产生较高的间质压力而阻碍药物进入肿瘤的屏障。这个 PDAC中致密的间质基质主要是细胞外基质(ECM)的过度产生所致 由胶原蛋白和透明质酸组成。透明质酸是由透明质酸合成酶合成的 (HASS)，并被透明质酸酶(HYALs)降解。我们之前的工作和其他研究已经 研究表明，BRD4蛋白是溴域和端外最重要的成员 结构域(BET)家族蛋白，在PDAC中高表达。BET蛋白是BET的“读者” 乙酰化的染色质标记。BET抑制剂的治疗也减少了PDAC中的肿瘤生长 老鼠模型。在这项拨款申请中，我们提出了我们的新假设：(1)BET蛋白质 抑制通过减少HA的产生减少了HA在PDAC肿瘤中的积聚。我们 进一步假设(2)BET抑制将阻断HA介导的运动受体(RHAMM)- 驱动致癌HA信号。这些假设建立在强大的初步数据基础上。我们 提出两个具体目标。目的1：研究BET蛋白调节血凝素水平的作用 PDAC肿瘤及其分子机制。目标2：测试BET的能力 阻断HA信号转导的抑制剂。这项建议包括房委会规管的创新概念 PDAC，具有很高的生物学和临床相关性和意义，具有潜在的 开发PDAC的新治疗策略。

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.