A novel ellipticine analog as a therapeutic candidate for acute myeloid leukemia

描述（由申请人提供）：现有治疗急性髓系白血病（AML）的药物不足，疗效差，副作用严重。对于5年生存率低于20% -50%的成年人来说，这尤其是个问题。AML的分化治疗在导致更有效和更少毒性的治疗方面具有重要的前景。AML是一种以未成熟骨髓细胞分化受阻为特征的疾病。白血病细胞经过终末分化后，就失去了增殖能力。分化治疗的潜力已经通过使用分化剂ATRA证明，用于AML的一个相对不常见的亚群，即急性早幼粒细胞白血病。使用ATRA， 75% -85%的急性早幼粒细胞白血病患者现在可以治愈。我们最近发现了一种新的分化诱导剂CLT731，它在体外表现出强大的白血病分化诱导活性，并在小鼠体内表现出活性的初步证据。CLT731是一种类似于椭圆素的药物，椭圆素是一种以前被发现具有抗肿瘤活性但也具有高毒性的药物。由于CLT731对白血病细胞具有优先活性，因此其毒性明显降低。这个I期项目的目的是：1)证明CLT731在小鼠AML模型系统中的前景；2)证明该化合物在体外患者样本上的活性；3)评估其潜在毒性。由于对新型AML治疗药物的巨大需求，特别是毒性降低的药物，这项工作有可能改善AML患者的生活质量。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): Existing therapeutic agents for Acute Myeloid Leukemia (AML) are inadequate to due poor efficacy and severe side effects. This is especially a problem in adults where the 5 year survival is less than 20-50%. Differentaition therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. AML is a disease characterized by the arrest of differentiation of immature myeloid cells. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The potential of differentiation therapy has been demonstrated by the use of the differentiation agent, ATRA, for one relatively uncommon subset of AML, acute promyelocytic leukemia. With the use of ATRA 75-85% of acute promyelocytic leukemia patients can now be cured. We have recently identified a novel differentiation-inducing agent, CLT731, that exhibits potent in vitro leukemia differentiation-inducing activity and preliminary evidence of mouse in vivo activity. CLT731 is an analogue of ellipticine, an agent that has perviously been found to have anti-tumor activity but also exhibits high toxicity. As CLT731 has preferential activity on leukemic cells, it appears to have a significantly reduced toxicity profile. The aims of this phase I project are to 1) demonstrate the promise of a CLT731 in mouse AML model systems 2) demonstrate the activity of this compound on patient samples in vitro and 3) to assess its potential toxicities. Due to the enormous need for novel AML therapeutics, especially agents with reduced toxicity, this work has the potential to improve the quality of life 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.