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)是最常见的成人急性白血病类型，也占儿童白血病的20%。AML的主流治疗方案是强化疗方案，毒性大，存活率一直很低。显然，需要更有效和更好的耐受性治疗。虽然随着伊马替尼在慢性粒细胞白血病治疗中的成功，靶向治疗受到了极大的关注，但对包括急性髓细胞白血病在内的其他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，在白血病发生中起重要作用。Flt3突变(Flt3MT)发生在约三分之一的AML患者中，并与不良预后有关。小分子Flt3TK抑制剂在临床试验中已经显示出抗白血病活性，尽管还没有取得持久的反应。基于RNAi的合成致死筛选在面对靶向治疗时，在识别维持白血病细胞活性的途径方面具有极大的潜力。通过使用基于全基因组RNAi的筛选，我们已经确定了在Flt3抑制剂CEP701存在的情况下，其抑制对Flt3MT AML细胞是致命的基因。我们将其抑制使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剂。ATM依赖通路的多个组成部分被鉴定为SLAM。基于初步的验证数据和治疗靶向的潜力，我们将重点关注ATM引导的代谢途径组件，作为开发新的联合疗法以更有效地治疗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.