AML differentiation therapy

急性髓系白血病（AML）是一种广泛的疾病，所有这些疾病都具有以下定义特征： 成熟停滞的白血病细胞。尽管反洗钱是最常见的形式， 在成人白血病中，40多年来标准治疗没有变化。的 所用的传统化疗剂表现出高毒性和低疗效， 56岁以上患者的生存期不到一年，其中只有20%的患者 活了两年。代替直接的细胞毒性剂，可以使用诱导细胞成熟的试剂。 AML细胞提供了一种靶向疾病的主要病理生理学的治疗方法。 我们以前确定了一种植物衍生的生物碱作为一个有前途的AML分化剂。我们 先导化合物对AML细胞表现出高效力， 人AML。机制研究表明，这种药物导致线粒体的扰动， 通过抑制硫氧还蛋白还原酶来代谢。在本提案中，我们建议 通过确定理想的给药途径和时间表来开发我们的先导化合物， 证实了我们的先导化合物在小鼠模型中的活性和作用机制， 人AML和鉴定用于该疗法的最佳AML患者。希望这项工作 将为AML患者带来更有效、更安全的治疗。

Acute Myeloid Leukemia (AML) is a broad range of disorders that all have the defining feature of leukemic cells with a maturation arrest. Despite the fact that AML is the most common form of leukemia in adults, there have been no changes in standard therapy in over 40 years. The traditional chemotherapeutics used exhibit both high toxicity and poor efficacy with a median survival in patients over the age of 56 of less than one year with only 20% of these patients surviving two years. Instead of directly cytotoxic agents, agents that induce the maturation of AML cells offers a therapeutic approach that targets the primary pathophysiology of the disease. We previously identified a plant derived alkaloid as a promising AML differentiation agent. Our lead compound exhibits high potency on AML cells and promising activity in a mouse model of human AML. Mechanistic studies suggest that this agent leads to perturbation of mitochondrial metabolism through inhibition of the enzyme thioredoxin reductase. In this proposal we propose to develop our lead compound by identifying ideal routes and schedules of dosing to mice, confirming the activity and mechanism of action of our lead compound in mouse models of human AML and identifying the optimal AML patients for this therapy. It is hoped that this work will lead to a more efficacious and safer therapy for AML patients.