Targeting Stroma to Improve Therapy of Pancreatic Adenocarcinoma

该RENEW/AL项目源于我们当前项目3中的发现，即富含胶原的促结缔组织压迫肿瘤中的血管。胰腺癌是一种高度促结缔组织增生性疾病，血管灌注量低，导致氧合和药物输送不良，低氧诱导耐药，肿瘤侵袭性增加。在PDAC中，促结缔组织增生症是由肿瘤相关的 成纤维细胞(TAFs)，由血管紧张素II(ATM)的几个下游效应物激活。ATII信号通过TSP1依赖的TGFB1激活、MEK/ERK激活和PDAC中SDF1a/CXCR4的表达刺激TAFs产生胶原。此外，SDF1a/CXCR4途径促进骨髓来源的细胞(如粒细胞)的募集，这些细胞分泌促纤维化分子，如TGFB1或自身产生胶原。我们推测，通过促进促结缔组织发育，TSP1/TGFB1 MEK/ERK和SDF1cx/CXCR4通路促进了低血管灌注率，从而限制了细胞毒药物在PDAC中的疗效。根据我们的初步数据，我们认为，特异性阻断这些通路-或主调节ATM受体1(AT1R)-减少PDAC中的促结缔组织增生，增加灌流、药物输送和氧合。在目标1中，我们将比较AT1R阻断剂氯沙坦和替米沙坦对PDAC结缔组织增生的影响，并确定它们对TSP1，TGFB1， SDFIa和ERK。然后，我们将研究直接阻断TGFB1、MEK和CXCR4对结缔组织发育的影响。在目标2中，我们将确定ATIR或TGFB1、MEK和CXCR4阻滞剂如何影响我们的PDAC模型的血液灌流、血管正常化、药物输送和缺氧。最后，在目标3中，我们将利用目标1和目标2中确定的最好的基质改良剂来提高PDAC(目标3)中小剂量(5FU和奥沙利铂)和大剂量(Abraxane)治疗的疗效。如果这些方法中的任何一种成功，我们的结果将为我们的临床合作者领导的未来PDAC临床试验奠定基础。

This renew/al Project arose from the discovery made in our current Project 3 that collagen-rich desmoplastic tissue compresses blood vessels in tumors. Pancreatic adenocarcinomas (PDACs) are highly desmoplastic and exhibit low vascular perfusion, which leads to poor oxygenation and drug delivery, hypoxia-induced drug resistance and increased tumor aggressiveness. In PDAC, desmoplasia is driven by tumor-associated fibroblasts (TAFs), which are activated by several downstream effectors of Angiotensin II (ATM). ATII signaling stimulates TAFs to produce collagen through TSP1-dependent TGFB1 activation, MEK/ERK activation and SDF1a/CXCR4 expression in PDAC. foreover, the SDF1a/CXCR4 pathway promotes the recruitment of bone marrow-derived cells (e.g., granulocytes), which secrete pro-fibrotic molecules such as TGFB1 or produce collagen themselves. We hypothesize that by promoting desmoplasia, the TSP1/TGFB1 MEK/ERK and SDF1cx/CXCR4 pathways promote poor vascular perfusion, which limits the efficacy of cytotoxics in PDAC. Based on our preliminary data, we propose that specific blockade of these pathways-or of the master regulator ATM receptor 1 (AT1R)-reduces desmoplasia and increases perfusion, drug delivery and oxygenation in PDAC. In Aim 1, we will compare the effects ofthe AT1R blockers losartan and telmisartan on desmoplasia in PDAC and determine their effects on the expression/activity of TSP1, TGFB1, SDFIa and ERK. We will then examine the effects of the direct blockade of TGFB1, MEK and CXCR4 on desmoplasia. In Aim 2 we will determine how ATIR or TGFB1, MEK and CXCR4 blockers affect blood perfusion, vascular normalization, drug delivery and hypoxia in our PDAC models. Finally, in Aim 3 we will utilize the best matrix modifiers identified in Aims 1 and 2 to enhance the therapeutic efficacy of small (5FU and oxaliplatin) and large (Abraxane) therapeutics in PDAC (Aim 3). If any of these approaches is successful, our results will form the foundation for future clinical trials in PDAC led by our clinical collaborators.