Response to PQ12 - Using thiol isomerase inhibitors to diminish cancer induced thrombosis

对 PQ12 的反应 - 使用硫醇异构酶抑制剂减少癌症诱发的血栓形成

• 批准号: 9813733
• 负责人: Daniel Robert Kennedy
• 金额: $ 16.41万
• 依托单位: WESTERN NEW ENGLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813733
• 关键词: A549; Aftercare; Anticoagulation; Antineoplastic Agents; Attenuated; Bleeding time procedure; Bleomycin; Blood Platelets; Blood coagulation; Brain; CA-125 Antigen; Cancer Etiology; Cancer Patient; Cancer cell line; Cause of Death; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Cisplatin; Clinical; Coagulation Process; Colon Carcinoma; Data; Doxorubicin; ERp57; Enzymes; Event; FDA approved; Fibrin; General Population; Generations; Goals; Hemorrhage; Immunocompetent; Isomerase; Kidney; Lung; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Molecular; Multiple Myeloma; Mus; Myocardial Infarction; Ovarian; Paclitaxel; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Platelet aggregation; Prostate; Protein Disulfide Isomerase; Pulmonary Embolism; Regimen; Relapse; Risk; Role; Safety; Serum; Sulfhydryl Compounds; Therapeutic; Thrombin; Thromboplastin; Thrombosis; Thrombus; Tumor Markers; Variant; Venous; Venous Thrombosis; Woman; Xenograft procedure; cancer cell; chemotherapeutic agent; chemotherapy; clinical effect; cytotoxic; endoplasmic reticulum glycoprotein p72; gemcitabine; high risk; inhibitor/antagonist; mortality; mortality risk; mouse model; neoplastic cell; novel; overexpression; phase 2 study; prevent; prophylactic; response; small molecule inhibitor; targeted treatment; tumor

Abstract In this proposal we aim to explore the involvement of thiol isomerases in cancer induced thrombosis and chemotherapy induced thrombosis. Cancer patients, particularly those receiving systemic chemotherapy, have a significantly increased risk of developing thrombosis, which has been estimated to be as high as 3 fold higher for arterial thrombosis and 50 fold higher for venous thrombosis when compared to the general population. This cancer-induced (or cancer-associated) thrombosis doubles the mortality risk of a patient and is considered the second leading cause of cancer death, responsible for upto 14% of cancer mortality. Despite the risks of thrombotic events, the molecular mechanisms behind cancer induced thrombosis are not well understood. There is significant variation in the risk of a thrombotic event occurring in a cancer patient and one of the major factors is the chemotherapeutic regimen they are receiving. Patients undergoing treatment with chemotherapeutic agents such as cisplatin, paclitaxel, doxorubicin and gemcitabine are known to have increased risk of thrombotic events. While the mechanisms by which thrombotic sequelae arise in cancer patients is unclear, both arterial and venous thrombotic events require thiol isomerases, including protein disulfide isomerase (PDI), ERp5, ERp57 and ERp72 to occur as inhibition of thiol isomerases will block both platelet aggregation, fibrin generation and thrombus formation. Recently a study observed that after treating lung cancer cells with cisplatin, the levels of PDI on the cell surface increased, which would be consistent with a pro coagulative state. This proposal would overcome the two major weaknesses of current prophylactic anticoagulation treatment, that current treatments only are indicated for arterial or venous thrombosis and have the potential to induce major bleeding. Our preliminary data presented demonstrated thiol isomerase inhibitors attenuate both arterial and venous thrombosis without increasing bleeding times in a mouse. In AIM 1 we will examine the effect of thiol isomerase inhibition to prevent or reduce tumor cell activated thrombosis and chemotherapy induced thrombosis. In AIM 2 we will establish the ability of thiol isomerase inhibition to prevent tumor induced thrombosis and chemotherapy induced thrombosis in a mouse model. Finally in AIM 3 we will perform a Phase II study of zafirlukast as a thiol isomerase-directed therapeutic in ovarian patients with tumor-marker only relapse.

抽象的 在本提案中，我们旨在探索硫醇异构酶在癌症诱导的血栓形成中的参与以及 化疗引起的血栓形成。癌症患者，特别是接受全身化疗的患者， 发生血栓形成的风险显着增加，据估计高达 3 倍 与一般人群相比，动脉血栓形成的风险高出 50 倍，静脉血栓形成的风险高出 50 倍。 这种癌症引起的（或癌症相关的）血栓形成使患者的死亡风险加倍，被认为 癌症死亡的第二大原因，占癌症死亡率的 14%。尽管存在风险 血栓事件，癌症诱发血栓形成背后的分子机制尚不清楚。 癌症患者发生血栓事件的风险存在显着差异，这是主要的原因之一 因素是他们正在接受的化疗方案。正在接受治疗的患者 已知化疗药物如顺铂、紫杉醇、阿霉素和吉西他滨具有 血栓事件的风险增加。 虽然癌症患者出现血栓后遗症的机制尚不清楚，但动脉和 静脉血栓事件需要硫醇异构酶，包括蛋白质二硫键异构酶 (PDI)、ERp5、ERp57 和 ERp72 的发生是因为硫醇异构酶的抑制会阻止血小板聚集、纤维蛋白生成和 血栓形成。最近的一项研究观察到，用顺铂治疗肺癌细胞后， 细胞表面的 PDI 增加，这与促凝血状态一致。 该提案将克服当前预防性抗凝治疗的两个主要弱点， 目前的治疗方法仅适用于动脉或静脉血栓形成，并且有可能诱发 大出血。我们提供的初步数据表明硫醇异构酶抑制剂可减弱两种动脉 和静脉血栓形成，而不增加小鼠的出血时间。在 AIM 1 中，我们将检查以下效果： 硫醇异构酶抑制可预防或减少肿瘤细胞活化血栓形成和化疗引起的 血栓形成。在 AIM 2 中，我们将建立硫醇异构酶抑制的能力，以防止肿瘤诱发 小鼠模型中的血栓形成和化疗诱导的血栓形成。最后在 AIM 3 中我们将执行 扎鲁司特作为硫醇异构酶定向治疗药物治疗具有肿瘤标志物的卵巢患者的 II 期研究 只会复发。