Hemostatic Factors Drive Prostate Cancer Pathogenesis

止血因素驱动前列腺癌发病机制

基本信息

批准号：
9262181
负责人：
JOSEPH S. PALUMBO
金额：
$ 35.69万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262181
关键词：
Accounting Alleles Alpha Cell American Animal Model Anticoagulation Antisense Oligonucleotides Automobile Driving Binding Blood Coagulation Factor Cancer Etiology Carcinoma Cell Line Cessation of life Chronic Clinical Clinical Research Clinical Trials Coagulation Process Coupling Data Development Disease Disease Progression Dysplasia Epithelial Cells Fibrin Fibrinogen Fibroblasts Gene Targeting Generations Genetic Predisposition to Disease Growth Hemophilia A Hemorrhage Hemostatic Agents Human Immunologics Incidence Integrins Intervention Knowledge Laboratories Leukocytes Life Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic to Mus Mutation Neoplasm Metastasis Pathogenesis Peptide Hydrolases Pharmacology Phase Play Polymers Primary Neoplasm Prostate Prostatic Neoplasms Proteins Prothrombin Reporting Research Risk Role Shapes Signal Transduction System Technology Testing Therapeutic Thrombin Thrombin Receptor Thromboembolism Warfarin base cell type comparative effective therapy experimental study in vivo inhibitor/antagonist innovation men mutant new therapeutic target next generation novel novel therapeutic intervention novel therapeutics pre-clinical prevent programs prostate carcinogenesis public health relevance targeted treatment tool transgenic adenocarcinoma of mouse prostate tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this research program is to define the mechanisms by which hemostatic system components contribute to prostate cancer pathogenesis. Prostate cancer is the second leading cause of cancer death in American men, accounting for approximately 30,000 deaths in the USA each year. There is a critical need to better understand the mechanisms underlying prostate cancer pathogenesis in order to develop new, effective therapies. Growing evidence suggests that prostate cancer pathogenesis is uniquely dependent on hemostatic factors, in that procoagulants not only drive metastatic potential, but also appear to strongly promote prostate tumorigenesis and tumor growth. Consistent with this view, multiple independent clinical studies have shown that reduced procoagulant function resulting from either hemophilia, or anticoagulation therapy to minimize thromboembolic risk results in a far lower incidence of prostate cancer. This proposal builds on strong preliminary studies in the PI's laboratory. Here, analyses of mice with either a gene-targeted mutation resulting in constitutively reduced prothrombin expression, or the use of novel antisense oligonucleotide (ASO) technology to pharmacologically lower prothrombin expression, both suggest that deficits at the level of prothrombin dramatically reduce prostate cancer growth in vivo and limit the formation of metastatic foci. The studies outlined in this proposal will buil on additional preliminary data suggesting that thrombin plays a multifaceted role in prostate cancer progression through distinct mechanisms involving thrombin signaling via PAR-1, as well as fibrin polymer formation. The proposed studies will use a combination of state-of-the-art gene-targeted mice and novel pharmacological tools to test the following hypotheses: (1) thrombin supports prostate cancer progression through multiple distinct mechanisms that support both early and late phases of disease progression, and therapeutic strategies directed at pro/thrombin constitute novel, safe, and effective means to impede prostate cancer growth and metastasis; (2) activation of PAR-1 expressed by both malignant prostate epithelial cells and carcinoma-associated fibroblasts promotes prostate cancer tumorigenesis and progression; (3) fibrin polymer, not soluble fibrinogen, is the form of the protein driving prostate cancer progression; (4) fibrin in the prostate tumor stroma promotes tumorigenesis and tumor growth by shaping the immunological tumor microenvironment through engagement of the leukocyte integrin αMβ2. The proposed studies will fill significant knowledge gaps in understanding the pathobiology of prostate cancer and the role of key coagulation factors in mediating tumorigenesis, tumor growth, and metastasis. Additionally, results generated through this proposal are likely to illuminate novel therapeutic targets and proof-of-principle strategies for limiting prostate cancer progression.

描述（由适用提供）：该研究计划的长期目标是定义止血系统成分有助于前列腺癌发病机理的机制。前列腺癌是美国男性癌症死亡的第二大主要原因，每年在美国造成约30,000人死亡。迫切需要更好地了解前列腺癌发病机理的基础机制，以开发新的有效疗法。越来越多的证据表明，前列腺癌的发病机理独特地取决于止血因素，因为proc仪不仅促进了转移性潜力，而且似乎强烈促进了前列腺肿瘤的发生和肿瘤的生长。与这种观点一致，多项独立的临床研究表明，降低了由血友病或抗凝治疗导致的凝凝胶功能，以最大程度地减少血栓性风险会导致前列腺癌的发生率要低得多。该提案以PI实验室的强大初步研究为基础。在此，对具有基因靶向突变的小鼠的分析，导致组成症降低了凝血酶蛋白的表达，或使用新型的反义寡核苷酸（ASO）技术来降低凝血酶蛋白的表达，这两者都表明，定义了在vivo中的前列腺素癌症水平上定义的，并在Vivo中降低了预测，并限制了限制的焦点。该提案中概述的将建立在其他初步数据的基础上，这表明凝血酶通过涉及通过PAR-1的凝血酶信号传导以及纤维蛋白聚合物形成的不同机制在前列腺癌进展中起多方面的作用。拟议的研究将使用最先进的基因靶向小鼠和新型药理学工具的结合来测试以下假设：（1）凝血酶通过多种不同的机制支持前列腺癌的进展，这些机制支持疾病进展的早期和晚期阶段，以及针对Pro/Thrombin Novel构成新颖和有效的癌症的疾病进展和治疗策略的早期阶段，（2）由恶性前列腺上皮细胞和与癌相关的成纤维细胞表达的PAR-1激活促进了前列腺癌的肿瘤发生和进展；（3）纤维蛋白聚合物而非可溶性纤维蛋白原，是驱动前列腺癌进展的蛋白质形式。（4）前列腺肿瘤基质中的纤维蛋白通过通过白细胞整合蛋白αMβ2的参与来塑造免疫学肿瘤微环境，从而促进肿瘤发生和肿瘤生长。拟议的研究将填补在理解前列腺癌病理生物学以及关键凝血因子在介导肿瘤发生，肿瘤生长和转移中的作用的显着知识差距。此外，通过该提案产生的结果可能会阐明新的治疗靶标和原则策略限制前列腺癌的进展。