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

项目摘要/摘要 对代谢紊乱的治疗调节已成为治疗急性白血病的一种成功的治疗策略 含有致癌异柠檬酸脱氢酶(IDH)突变的髓系白血病(AML)。抑制IDH结果 在白血病原始细胞的终末期髓系分化中，并导致FDA批准IDH1和IDH2抑制剂在 AML。然而，目前还没有代谢导向疗法来治疗IDH野生型AML，它代表着 大多数急性髓系白血病患者。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中一种以前未知的代谢脆弱性。抑制 在缺乏IDH的AML细胞中，这种酶的表达足以上调细胞AKG并促进髓系分化 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，以及利用AKG依赖的代谢最有效的基因背景也是如此。 提出的研究试图严格检验以下假设：1)治疗难治性TP53- 突变/复杂核型(CK)AML亚群可能对AKG扰动特别敏感，以及2) 依赖AKG的双加氧酶家族，可将5-甲基胞嘧啶(5mC)转化为5-羟甲基胞嘧啶 (5hmC)和IMPACT基因表达，以及其他染色质修饰酶，是AKG- 依赖分化。该研究计划将利用体外系统来表征AKG依赖 表观遗传学程序，在活体小鼠模型中检测OGDH作为TP53-突变体/CK AML的可能靶点，以及 患者样本/患者来源的异种移植以确定异常的AKG依赖的代谢是否维持人类 白血病。拟议的研究将扩大我们对代谢物在白血病中使用的生物学理解。 并提出了一种基于分化的策略来治疗常规缺乏的化疗难治性白血病 有针对性的致癌基因。申请者斯科特·米尔曼博士是纪念馆白血病服务的讲师 斯隆·凯特琳癌症中心(MSKCC)在他的基础上制定了一项为期5年的职业发展计划 分子生物学和生物化学背景，以及他在内科肿瘤学方面的临床培训。米尔曼医生会 在Scott Lowe博士的指导下进行拟议的研究，Scott Lowe博士是一位国际知名的 癌症遗传学，有培训成功的独立调查人员的良好记录，以开发新技能 在功能基因组学和白血病模型方面，这对他开发新的治疗方法的职业目标至关重要 恶性血液病的手术入路。这种指导，再加上理想的培训环境 在MSKCC提供的，将允许米尔曼博士实施拟议的研究计划并过渡到R01- 在学术背景下资助独立的医生兼科学家的职位。

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.