Targeting GSK3 in AML

急性髓性白血病（AML）是成人中最常见的白血病形式之一， 尽管治疗取得了进展，但成人的5年生存率低于20-50%， 在老年人中更低。在治疗一个相对不常见的亚群 AML，急性早幼粒细胞白血病，与所有反式维甲酸（ATRA）说明了伟大的 有望开发出具有更高功效和更低毒性的药物。利用ATRA，假定治愈 75-85%的患者是可能的。ATRA的显著成功源于AML是一种 以未成熟的骨髓细胞的分化停止为特征的疾病。ATRA 通过迫使白血病细胞成熟来克服这种分化障碍。不幸的是， ATRA在临床上对90-95%的AML患者无效。最近我们发现， 靶向激酶GSK 3是诱导AML分化的有希望的策略，特别是在 与ATRA结合。不幸的是，没有FDA批准的特定GSK 3抑制剂。 我们已经确定了一种高效和特异性的GSK 3抑制剂， 细胞和动物模型中的AML。在本提案中，我们将评估 这种GSK 3抑制剂，进行动物疗效研究，并确定其对原发性 患者样本。希望这项工作将导致一种新的分化疗法， 改善非APL白血病患者的预后。

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. Unfortunately, ATRA does not work clinically for 90-95% of AML patients. Recently we identified that targeting the kinase GSK3 is a promising strategy to induce AML differentiation, particularly in combination with ATRA. Unfortunately, there are no FDA approved specific GSK3 inhibitors. We have identified a highly potent and specific GSK3 inhibitor that exhibits promise against AML in cell and animal models. In this proposal, we will assess the pharmacologic properties of this GSK3 inhibitor, perform animal efficacy studies, and determine its effects on primary patient samples. It is hoped that this work will lead to a new differentiation therapy that can improve the prognosis of patients with non-APL leukemia.