Natural product-derived differentiation agents for AML

描述(申请人提供)：虽然AML是成人最常见的白血病之一，但成人的5年生存率不到20%-50%，老年人的5年生存率显著降低。全反式维甲酸(ATRA)治疗急性早幼粒细胞白血病(APL)是一种相对少见的AML亚型，取得了显著的成功，说明了分化治疗的巨大前景。使用全反式维甲酸，75-85%的患者有可能治愈，但仅限于这种罕见的AML亚群。ATRA的显著成功源于这样一个事实，即AML是一种以未成熟髓系细胞分化受阻为特征的疾病。全反式维甲酸通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经过终末分化后，就失去了增殖能力。我们最近发现，一种植物来源的生物碱具有诱导AML分化的能力，有望成为非APL白血病的AML治疗药物。这个第二阶段项目的主要目标是进行临床前疗效和毒性研究，以便将这种植物衍生生物碱的优化形式开发为临床制剂。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，这项工作有可能为AML患者带来急需的更有效、毒性更低和更好的耐受性治疗。 公共卫生相关性：该项目与公共卫生高度相关，因为它的主要目标是为急性髓系白血病患者开发一种既有效又低毒的新治疗方案。由于目前的AML治疗方法疗效差、毒副作用大，迫切需要新的治疗方法和治疗方法。

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.