Plant-derived differentiation agents for AML

描述（由申请人提供）：植物衍生化合物，特别是生物碱，历来是目前使用的治疗剂的成功来源。最近，一种植物衍生的生物碱被鉴定为有效的急性髓细胞白血病（AML）分化诱导化合物。AML的分化治疗在导致更有效和毒性更小的治疗方面具有重要的前景。虽然AML是成人中最常见的白血病形式之一，但成人的5年生存率低于20-50%，老年人的5年生存率明显更低。全反式维甲酸（ATRA）在治疗AML的一个相对罕见的亚组急性早幼粒细胞白血病方面取得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。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。该I期项目的目的是：1）在小鼠异种移植模型系统中证明新型植物衍生生物碱的前景; 2）证明该化合物及其类似物的体外活性; 3）鉴定具有强效AML分化活性的新型植物衍生生物碱。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确定和开发耐受性更好且更有效的新疗法。由于大多数AML患者的预后目前很差，因此非常需要新的治疗方法。

DESCRIPTION (provided by applicant): Plant-derived compounds, particularly alkaloids, have historically been a successful source of currently used therapeutics. Recently, a plant-derived alkaloid was identified that is a potent acute myeloid leukemia (AML) differentiation-inducing compound. Differentiation therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. 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 lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, 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. 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. The aims of this phase I project are to 1) demonstrate the promise of a novel plant-derived alkaloid in a mouse xenograft model system 2) demonstrate the activity of this compound and its analogues in vitro and 3) to identify novel plant-derived alkaloids with potent AML differentiation activity. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to a 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 identify and develop novel therapeutics for patients with Acute Myeloid Leukemia that are better tolerated and more efficacious. As the prognosis for most patients with AML is currently poor, there is a significant need for new therapies.