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

摘要 在这项建议中，我们旨在探讨硫醇异构酶在癌症诱导的血栓形成和 化疗导致血栓形成。癌症患者，特别是那些接受全身化疗的患者， 患血栓形成的风险显著增加，据估计，血栓形成的风险高达3倍 与普通人群相比，动脉血栓和静脉血栓的发病率分别高出50倍。 这种由癌症引起的(或与癌症相关的)血栓形成会使患者的死亡风险加倍，并被认为 癌症死亡的第二大原因，占癌症死亡的14%。尽管存在以下风险 血栓事件，癌症导致血栓形成的分子机制还不是很清楚。 癌症患者发生血栓事件的风险有很大的差异，而主要的 因子是他们正在接受的化疗方案。正在接受治疗的患者 已知的化疗药物如顺铂、紫杉醇、阿霉素和吉西他滨 血栓事件的风险增加。 虽然癌症患者发生血栓后遗症的机制尚不清楚，但动脉和 静脉血栓形成事件需要硫醇异构酶，包括蛋白二硫键异构酶(PDI)、ERp5、ERp57 和ERp72的发生，因为抑制硫醇异构酶将阻止血小板聚集，纤维蛋白生成和 血栓形成。最近的一项研究观察到，顺铂处理肺癌细胞后， 细胞表面的PDI增加，这与促凝血状态一致。 这一建议将克服目前预防性抗凝治疗的两大弱点， 目前的治疗方法仅适用于动脉或静脉血栓形成，并有可能导致 大出血。我们的初步数据显示，硫醇异构酶抑制剂可使双侧动脉变弱。 和静脉血栓形成，而不会增加老鼠的出血时间。在目标1中，我们将考察 抑制硫醇异构酶预防或减少肿瘤细胞激活的血栓形成和化疗 血栓形成。在AIM 2中，我们将建立硫醇异构酶抑制预防肿瘤诱导的能力 血栓形成和化疗诱导的小鼠血栓形成模型。最后，在AIM 3中，我们将执行 扎鲁司特作为硫醇异构酶导向治疗卵巢肿瘤标志物患者的II期研究 只是故态复萌。

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.