Reprogramming PDAC Stroma by Targeting Coagulation in the Tumor Microenvironment

项目摘要 这项研究计划的总体目标是确定治疗策略，以转换基质， 胰腺导管腺癌（PDAC）的化疗和免疫敏感的肿瘤微环境（TME）。 PDAC的特征在于促进肿瘤生长/侵袭的促结缔组织增生性基质， 胰腺癌细胞（PCC）和免疫抑制性TME。高度堆积的癌相关成纤维细胞 细胞外基质（CAF）和致密细胞外基质（ECM）是PDAC基质的标志， 交付障碍。几种基质成分已被靶向以增强药物递送，但最近的研究表明， 已经提出了间质的抗肿瘤作用，因为完全消融间质成分导致更多的 侵袭性肿瘤非常需要新的策略来重新编程基质而不损害其抗肿瘤活性。 角色中心假设是PDAC TME中的凝血系统可以靶向重编程 PDAC基质克服化学抗性、药物递送屏障和免疫抑制性TME。癌症- 据报道，相关凝血是PDAC中的关键功能性信号传导途径。值得注意的是， 凝血分子靶点，包括凝血酶、蛋白酶激活受体1（PAR 1）和纤维蛋白原/纤维蛋白， 在促进肿瘤进展和治疗抗性方面具有重要作用。 具体而言，假设凝血酶-PAR 1信号传导轴可被靶向以抑制PCC 生长/侵袭和CAF生长/纤维化。此外，凝血酶介导的纤维蛋白沉积可以靶向于 抑制药物递送屏障和免疫抑制性TAM活性，从而抑制抗肿瘤T细胞 活动这一假设将进行测试机制和评估的翻译潜力， 以下两个综合目的：目的1）机理研究：确定混凝的贡献 PDAC TME中的目标。具体来说，研究小组将确定凝血酶-PAR 1信号轴的作用， CAF介导的纤维化，凝血酶介导的纤维蛋白沉积对耐药，和PAR 1/纤维蛋白对 免疫抑制性TME。目的2）转化研究：评价药物的药理学抑制作用。 凝血靶点特别是，该团队将使用患者- 用FDA批准的凝血酶和PAR 1抑制剂和纤维蛋白原消耗剂衍生的PDAC模型。 药理学抑制的效果将反馈到目标1，以描述抑制的功效。 凝血靶点这项研究的结果将建立一个新的机械理解的作用， PDAC TME中的凝血活性。它将决定阻断凝血是否是一种有希望的治疗方法。 重新编程PDAC基质并最终抑制PCC/CAF生长和改善药物递送的策略 和功效。

PROJECT SUMMARY The overarching goal of this research program is to identify therapeutic strategies to convert the stroma of pancreatic ductal adenocarcinoma (PDAC) to a chemo- and immune-sensitive tumor microenvironment (TME). PDAC is characterized by a desmoplastic stroma that facilitates tumor growth/invasion, chemoresistance of pancreatic cancer cells (PCC), and immunosuppressive TME. Highly packed cancer-associated fibroblasts (CAFs) and dense extracellular matrix (ECM) are hallmarks of the PDAC stroma and constitute physical drug delivery barriers. Several stromal components have been targeted to enhance drug delivery, but recent studies have suggested anti-tumor roles for the stroma as complete ablation of stromal components leads to more aggressive tumors. New strategies are highly desired to reprogram stroma without compromising its anti-tumor roles. The central hypothesis is that the coagulation system in the PDAC TME can be targeted to reprogram PDAC stroma to overcome chemoresistance, drug delivery barriers, and immunosuppressive TME. Cancer- associated coagulation has been reported as a key functional signaling pathway in PDAC. Notably, several coagulation molecular targets, including thrombin, protease-activated receptor 1 (PAR1), and fibrinogen/fibrin, have been implicated in important roles contributing to tumor progression and therapeutic resistance. Specifically, it is hypothesized that the thrombin-PAR1 signaling axis can be targeted to suppress PCC growth/invasion and CAF growth/fibrosis. In addition, thrombin-mediated fibrin deposition can be targeted to suppress the drug delivery barrier and immunosuppressive TAM activities, which suppresses anti-tumor T cell activities. This hypothesis will be tested mechanistically and evaluated for translational potential by pursuing the following two integrated aims: Aim 1) Mechanistic Research: Determine the contribution of the coagulation targets in the PDAC TME. Specifically, the team will determine the role of thrombin-PAR1 signaling axis to CAF-mediated fibrosis, thrombin-mediated fibrin deposition on drug resistance, and PAR1/fibrin on the immunosuppressive TME. Aim 2) Translational Research: Evaluate the pharmacological inhibition of the coagulation targets. Especially, the team will expand the mechanistic understanding from Aim 1 using patient- derived PDAC models with FDA-approved inhibitors of thrombin and PAR1, and fibrinogen depleting agents. The effects of pharmacological inhibition will feedback to Aim 1 to delineate the efficacy of inhibiting coagulation targets. The outcome of this research will establish a new mechanistic understanding of the role of coagulation activities in the PDAC TME. It will determine whether blockade of the coagulation is a promising strategy to reprogram the PDAC stroma and, ultimately, suppress PCC/CAF growth and improve drug delivery and efficacy.