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

摘要

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.