Targeting Stroma to Improve Therapy of Pancreatic Adenocarcinoma

这个更新的项目源于我们目前的项目3中的发现，即富含胶原的结缔组织压迫肿瘤中的血管。胰腺腺癌（PDAC）是高度促结缔组织增生的并且表现出低血管灌注，这导致氧合和药物递送差、缺氧诱导的耐药性和增加的肿瘤侵袭性。在PDAC中，结缔组织增生是由肿瘤相关的 成纤维细胞（TAF），其被血管紧张素II（ATM）的几种下游效应物激活。ATII信号通过TSP 1依赖性TGFB 1激活、MEK/ERK激活和PDAC中SDF 1a/CXCR 4表达刺激TAF产生胶原。一直以来，SDF 1a/CXCR 4途径促进骨髓来源的细胞的募集（例如，粒细胞），其分泌促纤维化分子如TGFB 1或自身产生胶原蛋白。我们假设通过促进结缔组织增生，TSP 1/TGFB 1 MEK/ERK和SDF 1cx/CXCR 4通路促进血管灌注不良，这限制了细胞毒性药物在PDAC中的疗效。基于我们的初步数据，我们提出，这些途径的具体封锁-或主调节ATM受体1（AT 1 R）-减少结缔组织增生和增加灌注，药物输送和氧合PDAC。在目的1中，我们将比较AT 1 R阻断剂氯沙坦和替米沙坦对PDAC中结缔组织增生的影响，并确定它们对TSP 1，TGFB 1， SDFIa和ERK。然后，我们将研究直接阻断TGF β 1、MEK和CXCR 4对结缔组织增生的影响。在目标2中，我们将确定ATIR或TGFB 1、MEK和CXCR 4阻断剂如何影响PDAC模型中的血液灌注、血管正常化、药物递送和缺氧。最后，在目标3中，我们将利用目标1和2中确定的最佳基质改性剂来增强PDAC中小剂量（5 FU和奥沙利铂）和大剂量（Abraxane）治疗剂的疗效（目标3）。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PDAC未来临床试验奠定基础。

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.