Targeting FTO to treat acute myeloid leukemia

靶向FTO治疗急性髓系白血病

• 批准号: 10058254
• 负责人: Jianjun Chen
• 金额: $ 56.99万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058254
• 关键词: 11q23; Acute Myelocytic Leukemia; Basic Science; Binding; Biology; Blast Cell; CD34 gene; Cell Line; Cells; Cyclic GMP; Data; Development; Disease Progression; Enzyme Inhibition; Exhibits; FLT3 gene; Fatty acid glycerol esters; Genetic; Goals; Hematopoietic; Hematopoietic Neoplasms; Human; In Vitro; Lead; MLL-rearranged leukemia; Malignant Neoplasms; Malignant neoplasm of brain; Medical; Messenger RNA; Modeling; Modification; Molecular; Molecular Cytogenetics; Mus; Mutate; Myelogenous; NPM1 gene; Obesity; Oncogenic; Overweight; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Plant Roots; Play; Prognosis; Property; Proteins; Proteomics; RNA; RNA methylation; Refractory; Relapse; Renal carcinoma; Reporting; Research Design; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Specificity; Structure; Talents; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transcript; Translational Research; Treatment Efficacy; Treatment Failure; Validation; Variant; Xenograft procedure; acute myeloid leukemia cell; analog; anti-cancer; antitumor effect; base; cancer cell; cancer therapy; cancer type; clinical application; combinatorial; crosslinking and immunoprecipitation sequencing; design; epidemiology study; epitranscriptome; experience; in vivo; inhibitor/antagonist; innovation; leukemia; malignant breast neoplasm; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; obesity risk; overexpression; pharmacokinetics and pharmacodynamics; relapse patients; response; self-renewal; side effect; small molecule; small molecule inhibitor; stem; success; therapeutically effective; transcriptome sequencing

PROJECT SUMMARY (ABSTRACT): Title: Targeting FTO to treat acute myeloid leukemia Background: Acute myeloid leukemia (AML) is a major form of leukemia with unfavorable prognosis. With currently available therapies, over 70% of patients with AML cannot survival over five years. Thus, it is urgent to develop more effective novel therapeutics. N6-methyladenosine (m6A) modification is the most abundant internal modification in eukaryotic messenger RNAs, and can be removed by m6A demethylases such as FTO. Recently, we reported that, as an m6A demethylase, FTO plays a critical oncogenic role in AML pathogenesis and drug response (Li Z., et al. Cancer Cell. 2017). Moreover, we showed that by suppression of the FTO/m6A signaling, R-2-hydroxyglutarate (R-2HG) displays intrinsic and broad anti-leukemia effects (Su et al. Cell. 2018). Our unpublished data suggests that FTO may also play a role in the self-renewal of leukemia stem/initiating cells (LSCs/LICs). Thus, our results have shown the functional importance of FTO in AML pathogenesis and drug response, and highlight the therapeutic potential of targeting FTO and the associated RNA epitranscriptome to treat FTO-high AMLs, which account for >60% of total AML cases and are often associated with unfavorable prognosis. More recently, we have identified a highly effective/selective small-molecule FTO inhibitor, namely CS-1, which shows the highest anti-leukemia efficacy amongst a panel of 213 FTO inhibitor hits, with IC50 values around 100 nM in suppression of viability of human AML cells (primary AML cells and cell line cells). Moreover, we have also demonstrated that this compound binds directly to FTO protein and substantially prolongs survival of AML mice in vivo. In addition, we also showed that this FTO inhibitor can substantially sensitize FTO-high AML cells to other therapeutic agents. Objective/Hypothesis: Pharmacological inhibition of FTO with selective small molecule inhibitors alone or in combination with other anti-leukemia therapeutics is an effective novel treatment approach in AML. Specific Aims: (1) To optimize CS-1 and develop clinically applicable effective and selective FTO inhibitors; (2) To develop effective FTO inhibitor-based therapeutic strategies to treat unfavorable-risk FTO-high AMLs; and (3) To decipher the cellular and molecular mechanisms underlying the anti-AML efficacy of the FTO inhibitor(s). Study Design: 1) We will develop more effective CS-1 analogs, and then assess and compare their FTO- inhibition efficacy, selectivity, drug-like properties and therapeutic efficacy, and conduct PK/PD/toxicity studies for the top 2 compounds (Aim 1). 2) We will further use murine AML and patient-derived xeno-transplantation (PDX) AML models to assess the therapeutic efficacy of our top FTO inhibitor(s), alone or in combination with other therapeutic agents, in treating unfavorable-risk FTO-high AMLs (Aim 2). 3) We will assess the effect of genetic depletion or pharmaceutical inhibition of FTO on LSC/LIC self-renewal, and also decipher the molecular mechanism by which FTO inhibition or FTO depletion displays potent anti-leukemia effects (Aim 3).

项目摘要(摘要)： 标题：靶向FTO治疗急性髓系白血病 背景：急性髓系白血病(AML)是一种主要的白血病类型，预后不良。使用 目前可用的治疗方法，超过70%的AML患者无法存活超过5年。因此，当务之急是 开发更有效的新疗法。N6-甲基腺苷(M6A)修饰是最丰富的内部 真核信使RNA中的修饰，并可被m6A去甲基酶如FTO去除。最近， 我们报道，作为一种m6A去甲基酶，FTO在AML的发病机制和药物治疗中起着重要的致癌作用。 回应(李志等人)癌细胞。2017年)。此外，我们还表明，通过抑制FTO/m6A信号， R-2-羟基戊二酸(R-2HG)显示出内在的和广泛的抗白血病作用(Su等人)。牢房。2018年)。我们的 未发表的数据表明，FTO也可能在白血病干细胞/起始细胞的自我更新中发挥作用 (LSC/LIC)。因此，我们的结果表明了FTO在AML发病机制和药物中的功能重要性 反应，并强调靶向FTO和相关的RNA表位转录组的治疗潜力 治疗FTO-高AML，占AML病例总数的60%，通常与不良相关 预后。最近，我们发现了一种高效/选择性的小分子FTO抑制剂，即 CS-1，在213种FTO抑制剂中显示出最高的抗白血病效果，IC50值 约100 nM抑制人AML细胞(原代AML细胞和细胞系细胞)的活性。此外， 我们还证明了这种化合物直接与FTO蛋白结合，显著延长了存活期。 急性髓系白血病小鼠在活体内。此外，我们还表明，这种FTO抑制剂可以显著增敏FTO-High AML细胞转移到其他治疗药物。 目的/假设：选择性小分子抑制剂单独或联合应用对FTO的药理抑制作用 联合其他抗白血病药物是治疗AML的一种有效的新方法。 具体目标：(1)优化CS-1，开发临床适用、高效、选择性的FTO抑制剂； (2)开发以FTO抑制剂为基础的有效治疗策略，以治疗不良风险的FTO高AML；以及 (3)阐明FTO抑制剂S抗AML作用的细胞和分子机制。 研究设计：1)我们将开发更有效的CS-1类似物，然后评估和比较它们的FTO-1- 抑制效果、选择性、类药物特性和治疗效果，并进行PK/PD/毒性研究 对于前两个化合物(目标1)。2)我们将进一步使用小鼠急性髓系白血病和患者来源的异种移植 (PDX)急性髓细胞白血病模型评估我们的顶级FTO抑制剂(S)单独或联合应用的治疗效果 其他治疗药物，用于治疗不良风险的FTO-高AML(目标2)。3)我们将评估以下措施的效果 FTO对LSC/LIC自我更新的遗传耗竭或药物抑制，并破译分子 FTO抑制或FTO耗竭显示出强大的抗白血病作用的机制(目标3)。