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

基本信息

批准号：
10684842
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
项目类别：
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/10684842
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 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 Proliferating Reagent Refractory Research Research Personnel Resources Role Sampling Scientist Services Solid Neoplasm Specificity System TP53 gene TP53-mutant acute myeloid leukemia Testing Therapeutic Training Treatment Failure Tumor Suppression Tumor Suppressor Proteins Up-Regulation Work acute myeloid leukemia cell adverse outcome alpha ketoglutarate cancer genetics career career development chemotherapy clinical practice clinical training cytotoxicity drug discovery effective therapy functional genomics genetic approach genetic technology histone methylation human disease improved outcome in vivo inhibitor instructor leukemia leukemia treatment 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

项目摘要

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.

项目概要/摘要代谢失调的治疗性调节已成为急性发作的成功治疗策略含有致癌异柠檬酸脱氢酶 (IDH) 突变的骨髓性白血病 (AML)。 IDH结果的抑制白血病母细胞的终末骨髓分化，并导致 FDA 批准 IDH1 和 IDH2 抑制剂反洗钱。然而，目前还没有针对 IDH 野生型 AML 的代谢导向疗法，这代表大多数 AML 患者。本提案中提供的初步数据描述了 2- 氧化戊二酸脱氢酶 (OGDH)，一种催化转化的三羧酸 (TCA) 循环酶 α-酮戊二酸 (aKG) 转化为琥珀酰辅酶 A，这是 AML 中以前未知的代谢脆弱性。抑制这种酶的作用足以上调细胞 aKG 并驱动缺乏 IDH 的 AML 细胞的骨髓分化突变。然而目前，通过抑制 OGDH 促进细胞命运改变的分子机制仍然未知，利用 aKG 依赖性代谢最有效的基因型背景也是如此。拟议的研究旨在严格检验以下假设：1) 治疗难治性 TP53- 突变/复杂核型 (CK) AML 子集可能对 aKG 扰动特别敏感，并且 2) TET 家族的 aKG 依赖性双加氧酶，可将 5-甲基胞嘧啶 (5mC) 转化为 5-羟甲基胞嘧啶 (5hmC) 和影响基因表达以及其他染色质修饰酶，充当 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 依赖性表观遗传程序，体内小鼠模型，以检查 OGDH 作为 TP53 突变/CK AML 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的 aKG 依赖性代谢是否维持人类白血病。拟议的研究将扩大我们对白血病代谢物用途的生物学理解并提出基于分化的策略来治疗传统疗法缺乏的化疗难治性白血病可靶向癌基因。申请人斯科特·米尔曼博士，纪念馆白血病服务讲师斯隆凯特琳癌症中心 (MSKCC) 制定了一项 5 年职业发展计划分子生物学和生物化学背景，以及肿瘤内科临床培训。米尔曼博士将在国际知名专家 Scott Lowe 博士的指导下进行拟议的研究癌症遗传学在培训成功的独立研究人员以开发新技能方面拥有良好的记录在功能基因组学和白血病建模领域，这对于他开发新疗法的职业目标至关重要血液系统恶性肿瘤的治疗方法。这种指导，结合理想的培训环境由 MSKCC 提供，将使 Millman 博士能够执行拟议的研究计划并过渡到 R01- 在学术环境中资助独立的医师科学家职位。