Novel Biomarkers Predicting Blood Clots in Ovarian Cancer

预测卵巢癌血栓的新型生物标志物

• 批准号: 10733645
• 负责人: Vahid Afshar-Kharghan
• 金额: $ 63.41万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733645
• 关键词: Adjuvant Chemotherapy; Antibiotics; Anticoagulation; Antioxidants; Biochemical; Biological Markers; Blood; Blood Platelets; Blood coagulation; Blood specimen; Cancer Patient; Cells; Clinical; Data; Early Intervention; Fibrinolytic Agents; Gene Expression; Gene Expression Profile; General Population; Generations; Genes; Genetic Markers; Goals; Haplogroup; Hemorrhage; Hemostatic Agents; Injections; Institution; Laboratories; Ligation; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Methionine; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Moon; Morbidity - disease rate; Mus; Mutation; Neoadjuvant Therapy; Nuclear; Patients; Peptides; Plasma; Reactive Oxygen Species; Reagent; Risk; Risk Factors; Role; Sampling; Somatic Mutation; Specimen; Thrombophilia; Thrombosis; Thrombus; Tumor-Derived; University of Texas M D Anderson Cancer Center; Venous; Venous Thrombosis; biomarker identification; cancer cell; cancer diagnosis; cancer genome; carcinogenesis; chemotherapy; clinical database; cohort; extracellular; extracellular vesicles; genetic makeup; genetic risk factor; genetic variant; high risk; improved; inhibitor; microvesicles; mortality; mouse model; neutrophil; novel; novel marker; ovarian neoplasm; podoplanin; predictive marker; prevent; programs; prophylactic; small molecule; thrombotic; tumor; tumor DNA; venous thromboembolism; vesicular release

Project Summary/Abstract Venous thromboembolism (VTE) develops in about one-fourth of patients with ovarian cancer and is associated with significant morbidity and mortality. Chemotherapy increases VTE risk, but administration of prophylactic anticoagulation to all patients on chemotherapy is associated with a substantial risk of bleeding. Therefore, it is crucial to identify patients with a higher risk of VTE. In the University of Texas MD Anderson Cancer Center (MDACC) Ovarian Cancer Moon Shot program, we have assembled a cohort of 354 patients who have received neoadjuvant chemotherapy. The availability of tumor specimens, blood samples, and an extensive clinical database from these patients provides us a unique opportunity to investigate the novel predictive biomarkers for VTE in ovarian cancer. Most previous studies on cancer thrombosis analyzed clinical, demographic, or hemostatic factors already known to be risk factors for VTE in cancer patients instead of identifying tumor-specific prothrombotic factors. We will explore cancer cell products that increase VTE risk and particularly investigate the impact of cancer cell-derived podoplanin and mitochondria on VTE. We found mitochondria in plasma samples of cancer patients and showed that ovarian cancer cells release mitochondria (both free and microvesicle-embedded). Injection of mitochondria caused venous thrombi in mice, rich in neutrophils and neutrophil extracellular trap (NETs). We speculate that mitochondria-targeted antioxidants and antibiotics blocking the synthesis of chemotactic formylmethionine(fMet)-tagged peptides reduce cancer VTE. We found that podoplanin is expressed on ovarian cancer cells and tumor-derived extracellular vesicles (EVs), and its expression is increased by chemotherapy. Podoplanin-expressing EVs activate platelets, and their injection into mice causes platelet-rich venous thrombi. We propose that a small molecule blocking podoplanin interaction with platelets reduces cancer thrombosis. We will examine whether the number of mitochondria and concentration of podoplanin in plasma predict VTE risk in ovarian cancer patients receiving chemotherapy. We will investigate the effect of a mitochondria-targeted antioxidant, an antibiotic blocking synthesis of fMet peptides, and a podoplanin inhibitor on venous thrombosis in a murine model of IVC ligation. Finally, we will compare the mutation profile and mutation burden of mitochondria and nuclear genes in tumors of ovarian cancer patients with and without VTE to identify the genetic changes in cancer cells associated with an increased VTE risk.

项目摘要/摘要 静脉血栓栓塞（VTE）在大约四分之一的卵巢癌患者中发展 具有明显的发病率和死亡率。化学疗法增加了VTE风险，但预防性疗法 对所有化学疗法患者的抗凝治疗都与出血的很大风险有关。因此，是 对于确定VTE风险较高的患者至关重要。在德克萨斯大学医学博士安德森癌症中心 （MDACC）卵巢癌月球射击计划，我们组装了354例接受的患者的队列 新辅助化疗。肿瘤标本，血液样本和广泛的临床的可用性 这些患者的数据库为我们提供了一个独特的机会，可以调查新颖的预测生物标志物 VTE卵巢癌。大多数先前关于癌症血栓形成的研究分析了临床，人口统计学或 癌症患者中已经是VTE的止血因素，而不是鉴定肿瘤特异性 促血栓性因素。我们将探索增加VTE风险并特别研究的癌细胞产品 癌细胞衍生的Podoplanin和线粒体对VTE的影响。我们在血浆中发现线粒体 癌症患者的样本，表明卵巢癌细胞释放线粒体（既免费和 微覆盖物）。将线粒体注射引起小鼠静脉血栓，富含嗜中性粒细胞和 中性粒细胞外陷阱（网）。我们推测，线粒体靶向的抗氧化剂和抗生素 阻止趋化甲基硫氨酸（FMET）标记的肽的合成减少了癌症VTE。我们发现 podoplanin在卵巢癌细胞和肿瘤衍生的细胞外囊泡（EV）上表达，其 化学疗法增加表达。表达podoplanin的电动汽车激活血小板，并将其注入到 小鼠会导致血小板富含静脉血栓。我们提出，一个小分子阻止了与 血小板减少癌症血栓形成。我们将检查线粒体的数量和浓度是否 血浆中的Podoplanin预测接受化疗的卵巢癌患者的VTE风险。我们将调查 线粒体靶向抗氧化剂的作用，FMET肽的抗生素阻断合成和A 在IVC连接的鼠模型中，对静脉血栓形成的Podopoplanin抑制剂。最后，我们将比较 卵巢癌患者肿瘤中线粒体和核基因的突变概况和突变负担 有或没有VTE，可以确定与VTE风险增加有关的癌细胞的遗传变化。