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

摘要 在这个提议中，我们的目的是探索硫醇异构酶在癌症诱导的血栓形成中的参与， 化疗诱发血栓形成。癌症患者，特别是那些接受全身化疗的患者， 发生血栓形成的风险显著增加，据估计， 与一般人群相比，动脉血栓形成和静脉血栓形成高50倍。 这种癌症诱导的（或癌症相关的）血栓形成使患者的死亡风险加倍， 是癌症死亡的第二大原因，占癌症死亡率的14%。尽管有风险， 尽管癌症引起血栓形成事件，但癌症诱导血栓形成背后的分子机制尚未得到很好的理解。 在癌症患者中发生血栓形成事件的风险存在显著差异，并且其中一个主要的风险因素是血栓形成。 因素是他们正在接受的化疗方案。接受以下治疗的患者 已知化疗剂如顺铂、紫杉醇、阿霉素和吉西他滨具有 血栓形成事件的风险增加。 虽然在癌症患者中出现血栓性后遗症的机制尚不清楚，但动脉和 静脉血栓形成事件需要巯基异构酶，包括蛋白质二硫键异构酶（PDI）、ERp5、ERp57 和ERp72发生，因为硫醇异构酶的抑制将阻断血小板聚集、纤维蛋白生成和 血栓形成最近一项研究观察到，在用顺铂处理肺癌细胞后， 细胞表面的PDI增加，这与促凝状态一致。 这一建议将克服目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， 大出血我们提出的初步数据表明，硫醇异构酶抑制剂可以减弱动脉和 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 抑制巯基异构酶以预防或减少肿瘤细胞激活的血栓形成和化疗诱导的 血栓形成在AIM 2中，我们将建立硫醇异构酶抑制剂防止肿瘤诱导的能力。 血栓形成和化疗在小鼠模型中诱导血栓形成。最后，在AIM 3中，我们将执行 扎鲁司特作为硫醇异构酶导向治疗药物治疗卵巢癌患者的II期研究 只是复发。

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.