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

基本信息

  • 批准号:
    10458582
  • 负责人:
  • 金额:
    $ 83.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates of all cancers, and the highest rate of thromboembolic complications. The prothrombotic potential of PDAC has been directly linked to high-level expression of Tissue Factor (TF) by PDAC tumor cells that drives exuberant thrombin activity in circulation and in the tumor microenvironment. This proposal is based on evidence that aggressive tumor progression and thrombophilia in PDAC are integrally linked via key bi-directional mechanisms promoting tumor growth and procoagulant potential. Preliminary data suggests that high-level tumor cell TF activity leads to thrombin/PAR-1 signaling in PDAC tumor cells and cancer-associated fibroblasts (CAFs), driving local production of the plasminogen activation (PA) system components, urokinase plasminogen activator (uPA) and receptor (uPAR). Initial results also indicate that the PA system is a central player driving the bi-directional mechanisms of PDAC tumor progression and venous thromboembolic complications. These findings support the central hypothesis that targeting PA system components will limit PDAC progression as well as simultaneously and paradoxically suppress PDAC-associated thrombophilia. The proposed studies will directly define the feed forward mechanisms linking the PAR-1/uPA/uPAR axis to PDAC tumor growth and invasion and will also identify the feedback mechanisms by which uPA/uPAR/plasminogen drive thrombophilia in PDAC. This consortium is a collaboration of experts in the basic and clinical sciences of hemostasis, tumor biology, and bioengineering. The proposed studies will use multiple innovative approaches, including analysis of de novo PDAC in unique genetically-modified mice, a cutting-edge 3D biomimetic culture system, novel pharmacological tools, and translational patient-derived xenograft models to analyze human tumor cells and CAFs. This powerful collection of expertise and reagents will be used to test the following specific hypotheses: (1) PAR-1-driven expression of uPA and uPAR in PDAC tumors promotes cancer progression, and drives thrombosis by mediating the release of tumor-cell associated TF procoagulant activity that increases circulating procoagulant activity; (2) tumor cell-intrinsic PAR-1 activity supports PDAC invasion through induction of uPA/uPAR, while PAR-1 signaling by CAFs drives uPA/uPAR-mediated tissue remodeling associated with advanced PDAC; and (3) therapies targeting PA either alone or in combination with anticoagulation will significantly impede both PDAC tumor progression and the associated thrombophilia. The proposed studies will provide novel insights into the contribution of PAR-1/uPA/uPAR to PDAC pathobiology, illuminate key mechanisms coupling the PA system to PDAC-associated thrombophilia, and provide essential proof-of- principle data in experimental animals and with patient-derived material to facilitate translation of findings into new treatments for PDAC and cancer-associated thrombosis.
总结

项目成果

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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:
    10681313
  • 财政年份:
    2022
  • 资助金额:
    $ 83.42万
  • 项目类别:
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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 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:
    $ 83.42万
  • 项目类别:

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