Novel differentiation therapy for AML

描述（由申请人提供）：急性髓性白血病（AML）是成人中最常见的白血病之一，尽管治疗取得了进展，但成人的5年生存率低于20-50%，老年人的5年生存率更低。全反式维甲酸（ATRA）在治疗急性髓细胞白血病（AML）中一种相对罕见的亚型——急性早幼粒细胞白血病方面取得了显著的成功，这说明了具有更高疗效和更低毒性的药物的巨大前景。使用ATRA， 75-85%的患者可能被治愈。ATRA的显著成功源于AML是一种以未成熟骨髓细胞分化受阻为特征的疾病。ATRA通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经过终末分化后，就失去了增殖能力。这个I期项目的目的是展示一种新的核苷类似物的前景，这种核苷类似物具有有效的诱导分化活性，可用于治疗AML。该化合物将在细胞培养和骨髓移植小鼠异种移植实验中使用原代患者样本评估其分化活性。此外，还将分析这种有前途的化合物的潜在毒性，特别是骨髓毒性。由于分化疗法能够治疗白血病而不需要明显的细胞毒性，这项工作有可能为AML患者带来更有效、毒性更小、耐受性更好的治疗方法。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系白血病患者开发一种既有效又低毒的新疗法。由于目前的AML治疗药物具有低疗效和高毒性，因此迫切需要新的AML治疗方法。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults and despite advances in treatment 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 agents with greater efficacy and less toxicity. 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 aim of this phase I project is to demonstrate the promise of a novel nucleoside analogue with potent differentiation-inducing activity for the treatment of AML. This compound will be evaluated for differentiation activity using primary patient samples in both cell culture and bone marrow engraftment mouse xenograft experiments. In addition, this promising compound will be analyzed for potential toxicities, particularly myelotoxicity. 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 develop a novel therapy for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As the current AML therapeutics have low efficacy and high toxicities, there is a significant need for new therapies for AML.