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

基本信息

  • 批准号:
    10681313
  • 负责人:
  • 金额:
    $ 92.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结

项目成果

期刊论文数量(0)
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{{ truncateString('MATTHEW J FLICK', 18)}}的其他基金

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:
    10517972
  • 财政年份:
    2022
  • 资助金额:
    $ 92.8万
  • 项目类别:
2022 Plasminogen Activation and Extracellular Proteolysis Gordon Research Conference and Seminar
2022年纤溶酶原激活和细胞外蛋白水解戈登研究会议暨研讨会
  • 批准号:
    10386008
  • 财政年份:
    2021
  • 资助金额:
    $ 92.8万
  • 项目类别:
Mechanisms linking the plasminogen/fibrinogen axis to the pathogenesis of COVID-19
纤溶酶原/纤维蛋白原轴与 COVID-19 发病机制的联系机制
  • 批准号:
    10471424
  • 财政年份:
    2021
  • 资助金额:
    $ 92.8万
  • 项目类别:
Mechanisms linking the plasminogen/fibrinogen axis to the pathogenesis of COVID-19
纤溶酶原/纤维蛋白原轴与 COVID-19 发病机制的联系机制
  • 批准号:
    10676149
  • 财政年份:
    2021
  • 资助金额:
    $ 92.8万
  • 项目类别:
Mechanisms linking the plasminogen/fibrinogen axis to the pathogenesis of COVID-19
纤溶酶原/纤维蛋白原轴与 COVID-19 发病机制的联系机制
  • 批准号:
    10316657
  • 财政年份:
    2021
  • 资助金额:
    $ 92.8万
  • 项目类别:
Fibrin(ogen) control of metabolic inflammation and obesity
纤维蛋白(原)控制代谢炎症和肥胖
  • 批准号:
    10311076
  • 财政年份:
    2018
  • 资助金额:
    $ 92.8万
  • 项目类别:
Fibrin(ogen) control of metabolic inflammation and obesity
纤维蛋白(原)控制代谢炎症和肥胖
  • 批准号:
    10065070
  • 财政年份:
    2018
  • 资助金额:
    $ 92.8万
  • 项目类别:
Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis
靶向纤溶酶原激活系统以限制胰腺癌进展和相关血栓形成
  • 批准号:
    10458582
  • 财政年份:
    2018
  • 资助金额:
    $ 92.8万
  • 项目类别:
Fibrin(ogen) control of metabolic inflammation and obesity
纤维蛋白(原)控制代谢炎症和肥胖
  • 批准号:
    10083730
  • 财政年份:
    2018
  • 资助金额:
    $ 92.8万
  • 项目类别:
Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis
靶向纤溶酶原激活系统以限制胰腺癌进展和相关血栓形成
  • 批准号:
    10022502
  • 财政年份:
    2018
  • 资助金额:
    $ 92.8万
  • 项目类别:

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