SIRT5 as a Therapeutic Target in Acute Myeloid Leukemia

SIRT5 作为急性髓系白血病的治疗靶点

• 批准号: 9101779
• 负责人: Michael W. Deininger
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101779
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acyl CoA Dehydrogenases; Age; American; Anthracyclines; Apoptosis; Arsenic; Biological Assay; Blast Cell; Bone Marrow; Bone Marrow Cells; CD34 gene; CRISPR/Cas technology; Cancer Biology; Carbon; Carnitine; Cell Culture Techniques; Cell Death Inhibition; Cell Line; Cell Survival; Cells; Cessation of life; Clinical Treatment; Combined Modality Therapy; Cytarabine; Cytosol; Cytotoxic agent; DNA Sequence; Data; Defect; Dependence; Development; Diagnosis; Disease; Employee Strikes; Energy Metabolism; Engineering; Enoyl-CoA Hydratase; Environment; Enzymes; Future; Gap Junctions; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Genetic Screening; Genome; Glucose; Glutamine; Glycolysis; Goals; Growth; Hematopoietic Neoplasms; Human; Individual; Institutes; Intention; Knowledge; Lysine; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular Profiling; Mus; Mutate; Mutation; Mutation Spectra; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Prevalence; Proteins; Regimen; Relapse; Respiratory Chain; Role; Sampling; Somatic Mutation; Specimen; Stem cell transplant; Stromal Cells; Survival Rate; Therapeutic; Transferase; Translating; Translational Research; Tretinoin; Umbilical Cord Blood; Universities; Utah; Work; acyl-CoA dehydrogenase; base; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; deacylation; design; enzyme activity; etomoxir; fatty acid oxidation; improved; inhibitor/antagonist; innovation; knock-down; leukemia; leukemic stem cell; metabolic profile; metabolomics; mimetics; mutation screening; new therapeutic target; next generation sequencing; novel therapeutics; oligomycin sensitivity-conferring protein; outcome forecast; oxidation; patient subsets; potential biomarker; precision medicine; public health relevance; research study; response; small hairpin RNA; small molecule; small molecule inhibitor; standard of care; targeted treatment; therapeutic target; transcriptome sequencing; tumor metabolism; tumorigenesis; validation studies

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, with survival rates in younger patients at approximately 50%, but less than 20% in patients over 60 years old. Additionally, AML stem cells often survive chemotherapy in the protective environment of the bone marrow, causing relapse even in patients with a good initial response to therapy. The current standard of care, chemotherapy or stem cell transplant, has remained largely unchanged for more than three decades. Unfortunately, of the estimated 18,000 Americans diagnosed with AML every year, more than 10,000 will die of their disease, defining an urgent need for better and more targeted therapies. DNA sequencing has identified numerous mutations in AML patients, but as yet this knowledge has not translated into major therapeutic advances. This probably reflects the complexity of the disease and the fact that many of the mutated genes have proven difficult to target therapeutically. To overcome some of the limitations of past efforts, we have taken a function-first approach, where AML cells from patients are screened and thousands of genes are inactivated, one-by-one, so that we can identify those that are critical for AML cell survival. Importantly, our assays are done in the presence of bone marrow stromal cells to mimic the protective environment of the bone marrow. This screen has revealed that a subset of AML samples are dependent on the activity of SIRT5, a multifunctional enzyme that regulates vital metabolic pathways in the mitochondria and cytosol. In these cells, SIRT5 knockdown caused growth inhibition and cell death, while normal, healthy bone marrow cells were unaffected. We propose to use SIRT5 knockdown and metabolic profiling to determine other key survival pathways in AML stem cells with the intention of exploiting these pathways with small molecules. These data will be correlated with somatic mutation screening, gene expression analysis and metabolomics profiling to understand the mechanistic underpinnings of SIRT5 dependence. Our studies have the potential to establish proof of principle that SIRT5 is a therapeutic target in AML, providing a scientific rationale for the development of clinically-viabl SIRT5 inhibitors to treat AML and possibly other types of cancer. Importantly, mice with deletion of SIRT5 are viable and have no major defects, suggesting that SIRT5 inhibitors would be well tolerated.

 描述（申请人提供）：急性髓性白血病（AML）是一种侵袭性血癌，预后较差，年轻患者的生存率约为 50%，但 60 岁以上患者的生存率低于 20%。细胞通常在骨髓的保护环境中存活下来，即使对初始治疗反应良好的患者也会导致复发。目前的护理标准，化疗或干细胞移植，在超过一年的时间里基本保持不变。不幸的是，每年约有 18,000 名美国人被诊断出患有 AML，其中有超过 10,000 人会死于这种疾病，这表明迫切需要更好、更有针对性的治疗方法，DNA 测序已在 AML 患者中发现了许多突变。知识尚未转化为重大的治疗进展，这可能反映了该疾病的复杂性以及许多突变基因已被证明难以靶向治疗的事实，为了克服过去努力的一些局限性，我们采取了功能优先的方法。方法，对来自患者的 AML 细胞进行筛选，并逐一灭活数千个基因，以便我们能够识别对 AML 细胞存活至关重要的基因。重要的是，我们的测定是在骨髓基质细胞存在的情况下进行的，以模拟。该筛选显示，一部分 AML 样本依赖于 SIRT5 的活性，SIRT5 是一种调节线粒体和细胞质中重要代谢途径的多功能酶。导致生长抑制和细胞死亡，而正常、健康的骨髓细胞不受影响。我们建议使用 SIRT5 敲低和代谢分析来确定 AML 干细胞的其他关键生存途径，目的是利用这些数据来利用这些途径。与体细胞突变筛选、基因表达分析和代谢组学分析相关，以了解 SIRT5 依赖性的机制基础。我们的研究有可能建立 SIRT5 是治疗靶点的原理证明。在 AML 中，为开发临床上可行的 SIRT5 抑制剂来治疗 AML 和可能的其他类型的癌症提供了科学依据。重要的是，SIRT5 缺失的小鼠能够存活并且没有重大缺陷，这表明 SIRT5 抑制剂具有良好的耐受性。