Targeting FTO to treat acute myeloid leukemia

靶向FTO治疗急性髓系白血病

基本信息

批准号：
10296661
负责人：
Jianjun Chen
金额：
$ 55.89万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
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/10296661
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 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

项目摘要

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).

项目概要（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）是白血病的一种主要形式，预后不良。和目前可用的治疗方法，超过 70% 的 AML 患者无法存活超过五年。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修饰真核生物信使 RNA 中的修饰，并且可以被 m6A 去甲基酶（例如 FTO）去除。最近，我们报道，作为一种 m6A 去甲基化酶，FTO 在 AML 发病机制和药物中发挥着关键的致癌作用反应（Li Z., et al. Cancer Cell. 2017）。此外，我们发现通过抑制 FTO/m6A 信号传导， R-2-羟基戊二酸 (R-2HG) 显示出内在且广泛的抗白血病作用 (Su et al. Cell. 2018)。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 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 RNA 表观转录组的治疗潜力治疗 FTO 高 AML，此类病例占 AML 病例总数的 60% 以上，并且通常与不良预后相关预后。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，在一组 213 个 FTO 抑制剂中表现出最高的抗白血病功效，其 IC50 值约 100 nM 抑制人类 AML 细胞（原代 AML 细胞和细胞系细胞）的活力。而且，我们还证明该化合物可直接与 FTO 蛋白结合并显着延长存活时间 AML 小鼠体内。此外，我们还表明，这种 FTO 抑制剂可以显着提高 FTO-high 的敏感性。 AML细胞对其他治疗药物的影响。目的/假设：单独使用选择性小分子抑制剂或对 FTO 进行药理学抑制与其他抗白血病疗法联合使用是治疗 AML 的一种有效的新型治疗方法。具体目标：（1）优化CS-1，开发临床适用的有效、选择性FTO抑制剂； (2) 开发有效的基于 FTO 抑制剂的治疗策略来治疗不利风险的 FTO 高 AML；和 (3) 破译FTO抑制剂抗AML功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- 抑制功效、选择性、类药特性和治疗功效，并进行PK/PD/毒性研究对于前 2 个化合物（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，用于评估我们的顶级 FTO 抑制剂单独或联合使用的治疗效果其他治疗药物，用于治疗不利风险 FTO 高 AML（目标 2）。 3）我们将评估效果 FTO 的遗传耗竭或药物抑制对 LSC/LIC 自我更新的影响，并破译分子 FTO 抑制或 FTO 消耗显示出有效的抗白血病作用的机制（目标 3）。