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).

项目摘要（摘要）： 标题：针对FTO治疗急性髓样白血病 背景：急性髓样白血病（AML）是白血病的主要形式，预后不良。和 目前可用的疗法，超过70％的AML患者无法在五年内生存。因此，迫切需要 开发更有效的新颖疗法。 N6-甲基读二氨酸（M6A）修饰是最丰富的内部 真核信使RNA的修饰，可以通过M6A脱甲基酶（例如FTO）去除。最近， 我们报告说，作为M6A脱甲基酶，FTO在AML发病机理和药物中起关键的致癌作用 反应（Li Z.等，CancerCell。2017）。此外，我们证明了通过抑制FTO/M6A信号传导， R-2-羟基戊二酸（R-2HG）显示出内在和广泛的抗白血病效应（Su等人Cell。2018）。我们的 未发表的数据表明，FTO也可能在白血病/启动细胞的自我更新中发挥作用 （LSC/LICS）。因此，我们的结果表明FTO在AML发病机理和药物中的功能重要性 反应，并突出靶向FTO和相关的RNA表演组的治疗潜力 治疗FTO高AML，占AML总案例的60％，并且通常与不利有关 预后。最近，我们已经确定了高效/选择性的小分子FTO抑制剂，即 CS-1在213 FTO抑制剂命中的面板中显示出最高的抗白血病功效，IC50值 在抑制人AML细胞（原代AML细胞和细胞系细胞）生存力的抑制作用中约为100 nm。而且， 我们还证明了该化合物直接与FTO蛋白结合，并大大延长了生存 体内的AML小鼠的鼠标。此外，我们还表明该FTO抑制剂可以显着敏感FTO-HIGH AML细胞到其他治疗剂。 客观/假设：仅选择性小分子抑制剂对FTO的药理抑制作用或 与其他抗白血病疗法结合使用是AML中一种有效的新型治疗方法。 具体目的：（1）优化CS-1并开发临床适用的有效和选择性FTO抑制剂； （2）制定有效的基于FTO抑制剂的治疗策略，以治疗不利的风险FTO-HIGH AML；和 （3）破译FTO抑制剂抗AML功效的基础的细胞和分子机制。 研究设计：1）我们将开发更有效的CS-1类似物，然后评估和比较其FTO- 抑制功效，选择性，类似药物的特性和治疗功效，并进行PK/PD/毒性研究 对于前2个化合物（AIM 1）。 2）我们将进一步使用鼠AML和患者衍生的异种移植 （PDX）AML模型，以评估我们顶级FTO抑制剂的治疗功效，单独或与 其他治疗剂，在治疗不利的FTO-FTO高AML时（AIM 2）。 3）我们将评估 FTO对LSC/LIC自我更新的遗传耗竭或药物抑制，也破译了分子 FTO抑制或FTO耗竭表现出有效的抗白血病作用的机制（AIM 3）。