Targeting an ATM-dependent metabolic pathway and FLT3 for AML therapy

描述（申请人提供）：急性髓系白血病（AML）是最常见的急性成人白血病类型，也占儿童白血病的20%。AML的主流治疗包括高强度化疗方案，具有相当大的毒性，生存率仍然很低。显然，需要更有效、更耐受性更好的治疗方法。虽然靶向治疗因伊马替尼治疗慢性髓系白血病的成功而受到广泛关注，但治疗其他白血病（包括急性髓系白血病）的类似治疗方法并未产生长期缓解。FLT3是一种受体酪氨酸激酶（TK），一旦突变激活，已被证明在白血病发生中起重要作用。FLT3突变（FLT3MT）发生在大约三分之一的AML患者中，并与不良预后相关。小分子FLT3 TK抑制剂在临床试验中显示出抗白血病活性，尽管尚未实现持久的反应。在靶向治疗中，基于rnai的合成致死筛选在识别维持白血病细胞活力的途径方面具有巨大的潜力。通过基于rnai的全基因组筛选，我们已经确定了FLT3抑制剂CEP701存在时FLT3MT AML细胞的抑制是致命的基因。我们将抑制AML细胞对FLT3抑制敏感的基因产物称为急性髓系白血病合成致死的“slam”。atm依赖通路的多个组分被确定为slam。基于初步验证数据和治疗靶向的潜力，我们将重点关注atm导向的代谢途径组分，作为开发新型联合疗法以更有效治疗AML的有希望的靶点。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is the most common type of acute adult leukemia and also accounts for 20% of childhood leukemias. Mainstream treatment of AML consists of intensive chemotherapy regimens with considerable toxicity, and survival rates have remained very low. Clearly, more effective and better tolerated therapies are required. While targeted therapies have received much attention with the success of imatinib for chronic myeloid leukemia, similar therapeutic approaches for other leukemias, including AML, have not produced long-term remissions. FLT3 is a receptor tyrosine kinase (TK) that, once mutationally activated, has been shown to have an important role in leukemogenesis. FLT3 mutations (FLT3MT) occur in about one-third of AML patients and have been associated with a poor prognosis. Small-molecule FLT3 TK inhibitors have shown anti-leukemic activity in clinical trials, although durable responses have not been achieved. RNAi-based synthetic lethal screens have fantastic potential for the identification of pathways that maintain leukemia cell viability i the face of targeted therapies. By using a genome-wide RNAi-based screen, we have identified genes whose suppression is lethal to FLT3MT AML cells in the presence of the FLT3 inhibitor CEP701. We refer to gene products whose inhibition sensitizes AML cells to FLT3 inhibition as 'SLAMs' for Synthetic Lethal in Acute Myeloid leukemia. Multiple components of ATM-dependent pathways were identified as SLAMs. Based on preliminary validation data and the potential for therapeutic targeting, we will focus on ATM-directed metabolic pathway components as promising targets for the development of novel combination therapies to more effectively treat AML.