Targeting FTO to treat acute myeloid leukemia

靶向FTO治疗急性髓系白血病

• 批准号: 10531853
• 负责人: Jianjun Chen
• 金额: $ 55.86万
• 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/10531853
• 关键词: 11q23; Acute Myelocytic Leukemia; Basic Science; Binding; Biology; Blast Cell; CD34 gene; Cell Line; Cells; Cyclic GMP; Cytogenetics; Data; Development; Disease Progression; Enzyme Inhibition; Exhibits; FLT3 gene; Genetic; Goals; Hematopoietic Neoplasms; Human; In Vitro; MLL-rearranged leukemia; Malignant Neoplasms; Malignant neoplasm of brain; Medical; Medicine; Messenger RNA; Modeling; Modification; Molecular; Mus; Mutate; Myelogenous; NPM1 gene; Obesity; Oncogenic; Overweight; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Prognosis; Property; Protein Inhibition; Protein Overexpression; 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; cancer cell; cancer therapy; cancer type; clinical application; combinatorial; crosslinking and immunoprecipitation sequencing; design; druggable target; epidemiology study; epitranscriptome; experience; fat mass and obesity-associated protein; high risk; in vivo; inhibitor; innovation; leukemia; malignant breast neoplasm; manufacture; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pharmacokinetics and pharmacodynamics; pharmacologic; 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).

项目总结（摘要）： 标题：靶向FTO治疗急性髓系白血病 背景：急性髓细胞白血病（acute myeloid leukemia，AML）是一种预后不良的白血病.与 目前可用的疗法中，超过70%的AML患者不能存活超过5年。因此，迫切需要 开发更有效的新疗法。N6-甲基腺苷（m6 A）修饰是最丰富的内部修饰。 在真核生物信使RNA中，这种修饰可以通过m6 A脱甲基酶如FTO去除。最近， 我们报道，FTO作为一种m6 A去甲基化酶，在AML的发病机制和药物治疗中起着关键的致癌作用， 响应（Li Z.，等人Cancer Cell. 2017年）。此外，我们表明，通过抑制FTO/m6 A信号传导， R-2-羟基戊二酸（R-2 HG）显示出内在的和广泛的抗白血病作用（Su等人，Cell. 2018年）。我们 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 (LSCs/低收入国家）。因此，我们的结果表明FTO在AML发病机制和药物治疗中的功能重要性。 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，占总AML病例的60%以上，通常与不利的 预后最近，我们已经鉴定了一种高效/选择性小分子FTO抑制剂，即 CS-1，其在一组213个FTO抑制剂命中中显示出最高的抗白血病功效，具有IC 50值 约100 nM抑制人AML细胞（原代AML细胞和细胞系细胞）的活力。此外，委员会认为， 我们还证明了这种化合物直接与FTO蛋白结合， AML小鼠的体内。此外，我们还表明，这种FTO抑制剂可以显著增敏FTO-高， AML细胞与其他治疗剂的比较。 目的/假设：单独使用选择性小分子抑制剂或 与其他抗白血病治疗剂联合使用是AML中有效的新治疗方法。 具体目的：（1）优化CS-1，开发临床上可应用的、有效的、选择性的FTO抑制剂; (2)开发有效的基于FTO通道的治疗策略，以治疗不可排除风险的FTO高AML;以及 (3)解读FTO抑制剂抗AML疗效的细胞和分子机制。 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。 抑制效力、选择性、药物样性质和治疗效力，并进行PK/PD/毒性研究 对于前2种化合物（目标1）。2)我们将进一步使用小鼠AML和患者来源的异种移植 (PDX)AML模型，以评估我们的顶级FTO抑制剂单独或与 其他治疗药物，用于治疗高风险FTO AML（目的2）。3)我们将评估 FTO对LSC/LIC自我更新的基因耗竭或药物抑制，并破译了FTO对LSC/LIC自我更新的分子机制。 FTO抑制或FTO耗竭显示出有效的抗白血病作用的机制（目的3）。