Exploiting alpha-ketoglutarate-dependent metabolism for therapeutic benefit in acute myeloid leukemia

利用α-酮戊二酸依赖性代谢来治疗急性髓系白血病

• 批准号: 10523632
• 负责人: Scott Evan Millman
• 金额: $ 20.61万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523632
• 关键词: Acute Myelocytic Leukemia; Biochemistry; Biological; Bone Marrow; CRISPR/Cas technology; Cell Line; Cells; Characteristics; Chromatin; Chromosome abnormality; Citric Acid Cycle; Clinical; Complex; DNA Methylation; Data; Development Plans; Dioxygenases; Disease; Drug Targeting; Environment; Enzyme Inhibition; Enzymes; Epigenetic Process; Face; Failure; Family; Funding; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Genotype; Goals; Hematologic Neoplasms; Human; In Vitro; International; Investigation; Isocitrate Dehydrogenase; Karyotype; Ketoglutarate Dehydrogenase Complex; Leukemic Cell; Maintenance; Malignant Neoplasms; Mediating; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Mutation; Myelogenous; Oncogenes; Oncogenic; Patients; Phenotype; Physicians; Positioning Attribute; Pre-Clinical Model; Prognosis; Reagent; Refractory; Research; Research Personnel; Resources; Role; Sampling; Scientist; Services; Solid Neoplasm; Specificity; System; TP53 gene; TP53-mutant acute myeloid leukemia; Testing; Therapeutic; Training; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Work; acute myeloid leukemia cell; adverse outcome; alpha ketoglutarate; base; cancer genetics; career; career development; chemotherapy; clinical practice; cytotoxicity; drug discovery; effective therapy; functional genomics; genetic approach; genetic technology; histone methylation; human disease; improved outcome; in vivo; inhibitor; instructor; leukemia; mimicry; mouse model; mutant; new therapeutic target; novel strategies; novel therapeutic intervention; patient derived xenograft model; precursor cell; programs; skills; succinyl-coenzyme A; tool; tumor

PROJECT SUMMARY/ABSTRACT Therapeutic modulation of dysregulated metabolism has emerged as a successful therapeutic strategy for acute myeloid leukemia (AML) harboring oncogenic isocitrate dehydrogenase (IDH) mutations. Inhibition of IDH results in terminal myeloid differentiation of leukemic blasts and led to FDA-approval of IDH1 and IDH2 inhibitors in AML. However, there are currently no metabolism-directed therapies for IDH wild-type AML, which represents the majority of AML patients. Preliminary data presented in this proposal describe the identification of 2- oxoglutarate dehydrogenase (OGDH), a tricarboxylic acid (TCA) cycle enzyme which catalyzes the conversion of alpha-ketoglutarate (aKG) to succinyl CoA, as a previously unknown metabolic vulnerability in AML. Inhibition of this enzyme is sufficient to upregulate cellular aKG and drive myeloid differentiation in AML cells lacking IDH mutations. Currently however, the molecular mechanisms facilitating the change in cell fate with OGDH inhibition remain unknown, as do the genotypic contexts where exploiting aKG-dependent metabolism is most efficacious. The studies proposed seek to rigorously test the hypotheses that, 1) the treatment-refractory TP53- mutant/complex karyotype (CK) AML subset may be particularly sensitive to aKG perturbation, and 2) that the TET family of aKG-dependent dioxygenases which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and impact gene expression, among other chromatin modifying enzymes, serve as effectors of aKG- dependent differentiation. The research plan will utilize in vitro systems to characterize the aKG-dependent epigenetic program, in vivo mouse models to examine OGDH as a putative target in TP53-mutant/CK AML, and patient samples/patient-derived xenografts to determine if aberrant aKG-dependent metabolism sustains human leukemia. The proposed investigations will expand our biological understanding of metabolite use in leukemia and advance a differentiation-based strategy to treat chemotherapy-refractory leukemias that lack conventionally targetable oncogenes. The applicant, Dr. Scott Millman, an Instructor on the Leukemia Service at the Memorial Sloan Kettering Cancer Center (MSKCC), has devised a 5-year career development plan that builds upon his background in molecular biology and biochemistry, and his clinical training in medical oncology. Dr. Millman will conduct the proposed research under the mentorship of Dr. Scott Lowe, an internationally renowned expert in cancer genetics with a proven track record of training successful independent investigators, to develop new skills in functional genomics and leukemia modeling that are essential for his career goal of developing new therapeutic approaches for hematologic malignancies. This mentorship, combined with the ideal training environment provided at MSKCC, will allow Dr. Millman to carry out the proposed research program and transition to an R01- funded independent, physician-scientist position in an academic setting.

项目摘要/摘要 失调代谢的治疗调节已成为急性的成功治疗策略 髓样白血病（AML）具有致癌性异位酸盐脱氢酶（IDH）突变。抑制IDH结果 在白血病爆炸的终末髓样分化中，并导致IDH1和IDH2抑制剂在 AML。但是，目前尚无代表IDH野生型AML的代谢疗法 大多数AML患者。本提案中提供的初步数据描述了2-的识别 氧气脱氢酶（OGDH），一种三羧酸（TCA）循环，该酶催化转化率 作为AML中以前未知的代谢脆弱性，α-酮戊二酸（AKG）的α-酮（AKG）。抑制 该酶足以上调细胞AKG并驱动缺乏IDH的AML细胞中的髓样分化 突变。但是，目前，分子机制促进了OGDH抑制的细胞命运变化 仍然未知，与依赖AKG代谢的基因型环境最有效。 拟议的研究试图严格检验，即1）治疗难治性TP53-- 突变/复合核型（CK）AML子集可能对AKG扰动特别敏感，2） TET依赖AKG的双加氧酶的TET家族，这些酶将5-甲基环肽（5MC）转换为5-羟基甲基环霉素 （5HMC）和撞击基因表达，除其他修饰酶的染色质外，还可以作为Akg-的效应子 依赖分化。研究计划将利用体外系统来表征AKG依赖性 表观遗传程序，在体内小鼠模型中检查OGDH是TP53-突动剂/CK AML的推定目标，并且 患者样品/患者衍生的异种移植物，以确定异常依赖AKG的代谢是否维持人 白血病。拟议的调查将扩大我们对白血病代谢物使用的生物学理解 并促进基于差异化的策略，以治疗常规缺乏的化学疗法 - 饮食性白血病 可靶向的癌基因。申请人斯科特·米尔曼（Scott Millman）博士，纪念馆的白血病服务讲师 斯隆·凯特林（Sloan Kettering）癌症中心（MSKCC）制定了一项为期5年的职业发展计划，以他的 分子生物学和生物化学的背景以及他在医学肿瘤学方面的临床培训。米尔曼·威尔博士 在国际知名专家斯科特·洛（Scott Lowe）的指导下进行拟议的研究 癌症遗传学具有验证的培训成功的独立研究人员的记录，以发展新技能 在功能性基因组学和白血病建模中，这对于他的职业生涯目标至关重要 血液系统恶性肿瘤的方法。这种指导与理想的培训环境相结合 在MSKCC提供的将允许Millman博士执行拟议的研究计划，并过渡到R01- 在学术环境中获得了独立的，科学家的职位。