Reprogramming PDAC Stroma by Targeting Coagulation in the Tumor Microenvironment

通过靶向肿瘤微环境中的凝血来重编程 PDAC 基质

• 批准号: 10681313
• 负责人: MATTHEW J FLICK
• 金额: $ 92.8万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681313
• 关键词: Ablation; Animal Model; Biomimetics; Blood coagulation; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Cell Growth; Cancer Etiology; Cessation of life; Chemoresistance; Clinical; Coagulation Process; Collagen; Data; Deposition; Desmoplastic; Disease; Drug Delivery Systems; Drug resistance; Economics; Evaluation; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Feedback; Fibrin; Fibrinogen; Fibroblasts; Fibrosis; Goals; Growth; Healthcare; Healthcare Systems; Hyaluronan; Immune; Invaded; Knowledge; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular; Molecular Target; Outcome; Outcomes Research; PAR-1 Receptor; Pancreatic Ductal Adenocarcinoma; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Reagent; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Survival Rate; Syndrome; System; T-Lymphocyte; Testing; Therapeutic; Thrombin; Tissue Model; Translating; Translational Research; Treatment outcome; Tumor-associated macrophages; clinically relevant; drug efficacy; efficacy validation; improved; in vivo; inhibitor; novel strategies; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pharmacologic; programs; recruit; standard of care; therapeutically effective; therapy resistant; translational potential; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; vascular inflammation; venous thromboembolism

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.

项目摘要 该研究计划的总体目标是确定转换的治疗策略 胰腺导管腺癌（PDAC），用于化学和免疫敏感的肿瘤微环境（TME）。 PDAC的特征是脱落基质，可促进肿瘤生长/侵袭，化学耐药性 胰腺癌细胞（PCC）和免疫抑制性TME。高度包装癌症相关的成纤维细胞 （CAFS）和密集的细胞外基质（ECM）是PDAC基质的标志，构成物理药物 送货障碍。几个基质​​成分已被针对增强药物的递送，但是最近的研究 由于基质成分的完整消融会导致更多的抗肿瘤作用 侵略性肿瘤。新策略非常需要重新编程基质而不损害其抗肿瘤 角色。中心假设是PDAC TME中的凝结系统可以针对重编程 PDAC基质以克服化学耐药性，药物输送障碍和免疫抑制性TME。癌症- 相关凝血已报告为PDAC中的关键功能信号通路。值得注意的是，有几个 凝血分子靶标，包括凝血酶，蛋白酶激活的受体1（PAR1）和纤维蛋白原/纤维蛋白， 与肿瘤进展和治疗性抗性有助于重要作用有关。 具体而言，假设凝血酶-Par1信号轴可以靶向抑制PCC 生长/入侵和CAF生长/纤维化。另外，凝血酶介导的纤维蛋白沉积可以针对 抑制药物输送障碍和免疫抑制性TAM活性，从而抑制抗肿瘤T细胞 活动。该假设将通过机理测试，并通过追求转化潜力进行评估 以下两个综合目的：目标1）机械研究：确定凝血的贡献 PDAC TME中的目标。具体而言，团队将确定凝血酶-Par1信号轴的作用 CAF介导的纤维化，凝血酶介导的耐药性纤维蛋白沉积以及PAR1/纤维蛋白在 免疫抑制TME。目的2）翻译研究：评估对药理的抑制 凝血目标。特别是，团队将使用患者从AIM 1扩大机械理解 - 带有FDA批准的凝血酶和PAR1抑制剂的PDAC模型，以及纤维蛋白原消耗剂。 药理学抑制的作用将反馈到目标1来描述抑制的功效 凝血目标。这项研究的结果将建立对 PDAC TME中的凝血活性。它将确定凝结的封锁是否是有前途的 重新编程PDAC基质并最终抑制PCC/CAF增长并改善药物递送的策略 和功效。