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.

项目概要/摘要 大约四分之一的卵巢癌患者会出现静脉血栓栓塞 (VTE)，并且与 具有显着的发病率和死亡率。化疗会增加 VTE 风险，但预防性用药 所有接受化疗的患者进行抗凝治疗都存在很大的出血风险。因此，它是 对于识别 VTE 风险较高的患者至关重要。德克萨斯大学 MD 安德森癌症中心 (MDACC) 卵巢癌登月计划，我们组建了一个由 354 名接受过卵巢癌治疗的患者组成的队列 新辅助化疗。肿瘤标本、血液样本和广泛的临床研究的可用性 这些患者的数据库为我们提供了一个独特的机会来研究新型预测生物标志物 卵巢癌中的 VTE。大多数先前关于癌症血栓形成的研究都分析了临床、人口统计学或 已知止血因素是癌症患者 VTE 的危险因素，而不是确定肿瘤特异性 促血栓因素。我们将探索增加 VTE 风险的癌细胞产品，并特别研究 癌细胞来源的足足蛋白和线粒体对 VTE 的影响。我们在血浆中发现了线粒体 研究人员对癌症患者的样本进行了研究，结果表明卵巢癌细胞释放线粒体（游离线粒体和线粒体） 微泡嵌入）。注射线粒体引起富含中性粒细胞和中性粒细胞的小鼠静脉血栓 中性粒细胞胞外陷阱（NET）。我们推测靶向线粒体的抗氧化剂和抗生素 阻断趋化甲酰甲硫氨酸 (fMet) 标记肽的合成可减少癌症 VTE。我们发现 平足蛋白在卵巢癌细胞和肿瘤来源的细胞外囊泡 (EV) 上表达，及其 化疗可增加表达。表达足平蛋白的 EV 激活血小板，并将其注射到 小鼠引起富含血小板的静脉血栓。我们提出一种小分子阻断足足蛋白与 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 血浆中的足足蛋白可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、阻断 fMet 肽合成的抗生素以及 平足蛋白抑制剂对 IVC 结扎小鼠模型中静脉血栓形成的影响。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谱和突变负荷 有或没有 VTE，以确定与 VTE 风险增加相关的癌细胞基因变化。