Natural product-derived differentiation agents for AML

描述（由申请人提供）：尽管AML是成人中最常见的白血病形式之一;成人的5年生存率低于20-50%，老年人的5年生存率显著降低。用全反式维甲酸（ATRA）治疗AML的一个相对不常见的子集急性早幼粒细胞白血病（APL）的显著成功说明了分化治疗的巨大前景。使用ATRA，75-85%的患者的假定治愈是可能的，但仅限于这种罕见的AML子集。ATRA的显著成功源于AML是一种以未成熟骨髓细胞分化停滞为特征的疾病。ATRA通过迫使白血病细胞成熟来克服这种分化障碍。在白血病细胞经历终末分化后，它们失去了增殖能力。我们最近发现，一种植物衍生的生物碱有希望作为非APL白血病的AML治疗药物，因为它能够诱导有效的AML分化。这个第二阶段项目的主要目的是进行临床前疗效和毒性研究，以将我们优化形式的这种植物衍生生物碱开发成临床药物。由于分化疗法能够在不需要明显细胞毒性的情况下治疗白血病，因此这项工作有可能为AML患者带来急需的更有效、毒性更小和耐受性更好的疗法。 公共卫生相关性：该项目与公共卫生高度相关，因为其主要目标是为急性髓性白血病患者开发一种既有效又低毒的新型治疗方案。由于目前的AML治疗剂具有差的疗效和高毒性，因此非常需要用于AML的新疗法和治疗方法。

DESCRIPTION (provided by applicant): Though AML is one of the most common forms of leukemia in adults; the 5 year survival is less than 20-50% in adults and significantly lowers in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia (APL), with all trans- retinoic acid (ATRA) illustrates the great promise for differentiation therapy. Utilizing ATRA, the presumed cure of 75-85% of patients is possible but only for this rare AML subset. ATRA's remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cells. ATRA overcomes this block in differentiation by forcing leukemic cells to mature. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. We have recently found that a plant-derived alkaloid holds promise as an AML therapeutic for non-APL leukemia due to its ability to induce potent AML differentiation. The major aims of this phase II project are to perform preclinical efficacy and toxicity studies in order to develop our optimized form of this plant-derived alkaloid into a clinical agent. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to much needed more efficacious, less toxic, and better tolerated therapy for patients with AML. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to develop a novel therapeutic regimen for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As current AML therapeutics has poor efficacy and high toxicities, there is a significant need for new therapies and therapeutic approaches for AML.