Novel differentiation therapy for AML

描述(申请人提供)：急性髓系白血病(AML)是成人最常见的白血病之一，尽管治疗方法有所进步，但成人的5年生存率不到20%-50%，老年人的5年生存率明显低于20%-50%。全反式维甲酸(ATRA)治疗急性早幼粒细胞白血病(AML)一种相对不常见的亚型的显著成功，表明了更有效、毒性更低的药物的巨大前景。利用全反式维甲酸，75%-85%的患者有可能被假定治愈。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。这一第一阶段项目的目的是展示一种具有强大分化诱导活性的新型核苷类似物用于治疗急性髓细胞白血病的前景。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始患者样本进行分化活性评估。此外，这种有希望的化合物将被分析潜在的毒性，特别是骨髓毒性。由于分化治疗能够在不需要明显细胞毒性的情况下治疗白血病，这项工作有可能为急性髓细胞白血病患者带来一种更有效、毒性更低、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疗法。由于目前的AML治疗方法疗效低、毒副作用大，因此迫切需要新的治疗方法。

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.