Novel Biomarkers Predicting Blood Clots in Ovarian Cancer

项目摘要/摘要 静脉血栓栓塞症(VTE)发生在大约四分之一的卵巢癌患者中，并与 发病率和死亡率都很高。化疗会增加静脉血栓形成的风险，但预防性治疗 对所有接受化疗的患者进行抗凝治疗会增加出血的风险。因此，它是 对识别VTE风险较高的患者至关重要。在德克萨斯大学MD安德森癌症中心 (MDACC)卵巢癌登月计划，我们已经召集了354名接受了 新辅助化疗。肿瘤标本、血液样本的可用性以及广泛的临床应用 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的预测生物标志物 卵巢癌的静脉血栓栓塞术。以前大多数关于癌症血栓形成的研究都分析了临床、人口统计学或 已知的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 血栓前因子。我们将探索增加VTE风险的癌细胞产品，并特别研究 癌细胞衍生的泊多普宁和线粒体对静脉血栓栓塞症的影响。我们在血浆中发现了线粒体 癌症患者的样本，并显示卵巢癌细胞释放线粒体(包括游离和 微囊包埋)。线粒体注射引起小鼠静脉血栓，富含中性粒细胞和 中性粒细胞胞外捕获器(NETS)。我们推测线粒体靶向的抗氧化剂和抗生素 阻断趋化甲硫氨酸(FMet)标记多肽的合成可减少癌症VTE。我们发现 泊多拉宁在卵巢癌细胞和肿瘤细胞外小泡(EVS)上表达，其 化疗使其表达增强。表达泊多拉宁的EV激活血小板，并将其注射到 老鼠会导致富含血小板的静脉血栓。我们提出了一个阻断泊多普宁与其相互作用的小分子 血小板可减少癌症血栓形成。我们将检查线粒体的数量和浓度是否 血浆泊多拉宁可预测接受化疗的卵巢癌患者的VTE风险。我们会调查的 线粒体靶向抗氧化剂、阻断fMet多肽合成的抗生素以及 泊多拉宁抑制剂对下腔静脉结扎小鼠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及突变负荷 有无静脉血栓栓塞术，以确定与静脉血栓栓塞术风险增加相关的癌细胞基因变化。

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.