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.

项目总结/摘要 代谢失调的治疗性调节已经成为急性胰腺炎的成功治疗策略。 携带致癌异柠檬酸脱氢酶（IDH）突变的髓性白血病（AML）。IDH抑制结果 在白血病原始细胞的终末髓样分化中，并导致FDA批准IDH 1和IDH 2抑制剂， 急性髓细胞白血病然而，目前还没有针对IDH野生型AML的代谢导向疗法，这代表了 大多数AML患者。本提案中提供的初步数据描述了2- 氧代戊二酸脱氢酶（OGDH），一种三羧酸（TCA）循环酶，其催化戊二酸的转化， α-酮戊二酸（aKG）转化为琥珀酰CoA，作为AML中以前未知的代谢脆弱性。抑制 这种酶足以上调细胞aKG并驱动缺乏IDH的AML细胞的髓样分化 突变。然而，目前，促进OGDH抑制改变细胞命运的分子机制 仍然未知，因为利用aKG依赖性代谢最有效的基因型背景也是如此。 提出的研究试图严格检验以下假设：1）难治性TP 53- 突变/复杂核型（CK）AML亚群可能对aKG扰动特别敏感，2）突变/复杂核型（CK）AML亚群可能对aKG扰动特别敏感， 将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶的aKG依赖性双加氧酶的泰特家族 （5 hmC）和影响基因表达，以及其他染色质修饰酶，作为aKG的效应子。 依赖分化该研究计划将利用体外系统来表征aKG依赖性 表观遗传学程序，体内小鼠模型，以检查OGDH作为TP 53突变体/CK AML中的推定靶标，以及 患者样本/患者来源的异种移植物，以确定异常aKG依赖性代谢是否维持人类 白血病拟议的调查将扩大我们的代谢物在白血病中使用的生物学理解 并提出一种基于分化的策略来治疗化疗难治性白血病， 靶向癌基因申请人斯科特·米尔曼博士是纪念医院白血病服务的指导员 斯隆凯特琳癌症中心（MSKCC），设计了一个5年的职业发展计划，建立在他的基础上， 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训练。米尔曼博士将 进行拟议的研究的指导下博士斯科特劳，一个国际知名的专家， 癌症遗传学，在培训成功的独立研究人员方面有着良好的记录， 在功能基因组学和白血病建模，这是必不可少的，他的职业目标，开发新的治疗 血液恶性肿瘤的治疗方法。这种指导，结合理想的培训环境， 在MSKCC提供，将允许米尔曼博士进行拟议的研究计划，并过渡到R 01- 在学术环境中获得资助的独立的医生科学家职位。