Reprogramming PDAC Stroma by Targeting Coagulation in the Tumor Microenvironment

项目总结 这项研究计划的主要目标是确定治疗策略，以转化基质 胰腺导管腺癌(PDAC)向化疗和免疫敏感的肿瘤微环境(TME)转化。 PDAC的特征是结缔组织间质促进肿瘤的生长/侵袭，化疗耐药 胰腺癌细胞(PCC)和免疫抑制药TME。高度聚集的癌症相关成纤维细胞 (CAF)和致密细胞外基质(ECM)是PDAC基质的特征，构成物理药物 交付障碍。几种基质成分已被靶向增强药物传递，但最近的研究 已经提出了间质的抗肿瘤作用，因为完全消融间质成分会导致更多 侵袭性肿瘤。人们迫切需要新的策略来在不损害其抗肿瘤的情况下重新编程间质 角色。中心假设是PDAC TME中的凝血系统可以被靶向重新编程 PDAC基质，以克服化疗耐药性、药物输送障碍和免疫抑制TME。癌症-- 相关凝血已被报道为PDAC中的一条关键的功能信号通路。值得注意的是，有几个 凝血分子靶标，包括凝血酶、蛋白酶激活受体1(PAR1)和纤维蛋白原/纤维蛋白， 参与了肿瘤进展和治疗耐药的重要作用。 具体地说，假设凝血酶-PAR1信号轴可以靶向抑制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 抑制药物传递障碍和免疫抑制活性，从而抑制抗肿瘤T细胞 活动。这一假设将被机械地检验，并通过追求 以下两个综合目标：目标1)机理研究：确定混凝的贡献 PDAC TME中的目标。具体地说，该团队将确定凝血酶-PAR1信号轴在 CAF介导的纤维化，凝血酶介导的纤维蛋白沉积在耐药中的作用，以及PAR1/纤维蛋白在 免疫抑制药TME。目的2)翻译研究：评价丹参的药理抑制作用 凝固靶。特别是，团队将使用患者-扩展目标1中的机械性理解- 衍生的PDAC模型含有FDA批准的凝血酶和PAR1抑制剂以及纤维蛋白原耗竭药。 药理抑制的效果将反馈到目标1，以描述抑制的效果 凝固靶。这项研究的结果将建立一个新的机制的角色的理解 PDAC TME中的凝血活性。这将决定阻断凝血是否是一种有希望的 对PDAC基质重新编程并最终抑制PCC/CAF生长和改善药物输送的策略 和药效。

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.