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: 9250106
• 负责人: Michael W. Deininger
• 金额: $ 16.46万
• 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/9250106
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acyl CoA Dehydrogenases; Age; Alpha Cell; American; Anthracyclines; Apoptosis; Arsenic; Biological Assay; Blast Cell; Bone Marrow; Bone Marrow Cells; CD34 gene; CRISPR/Cas technology; Cancer Biology; Carbon; Carnitine; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Clinical Treatment; Combined Modality Therapy; Cultured Cells; Cytarabine; Cytosol; Cytotoxic agent; DNA sequencing; 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; Hematologic Neoplasms; Hematopoietic Neoplasms; Human; Individual; Institutes; Intention; Knowledge; Lysine; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular Profiling; Molecular Target; Mus; Mutate; Mutation; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Prevalence; Proteins; Regimen; Relapse; Respiratory Chain; Role; Sampling; Somatic Mutation; Specimen; Stem cell transplant; Stromal Cells; Supporting Cell; 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; clinical development; deacylation; design; enzyme activity; etomoxir; experimental study; 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; 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（由适用提供）：急性髓样白血病（AML）是一种侵略性的血液癌，预后较差，年轻患者的存活率约为50％，但60岁以上的患者不到20％。此外，AML干细胞经常在骨髓保护环境中的化学疗法中幸存下来，即使对治疗的初始反应良好的患者也会缓解。当前的护理标准，化学疗法或干细胞移植已经在三十年中一直保持不变。不幸的是，在每年被诊断出患有AML的18,000名美国人中，有10,000多人将死于其疾病，这确定了迫切需要更好，更有针对性的疗法。 DNA测序已经确定了AML患者的大量突变，但到目前为止，这些知识尚未转化为主要的治疗进展。这可能反映了该疾病的复杂性以及许多突变基因被证明难以靶向理论的事实。为了克服过去努力的某些局限性，我们采取了一种功能优先的方法，其中筛选了来自患者的AML细胞，数千个基因被逐一灭活，因此我们可以识别出对AML细胞存活至关重要的基因。重要的是，我们的评估是在骨髓基质细胞存在下进行的，以模仿骨髓的受保护环境。该屏幕表明，AML样品的子集取决于SIRT5的活性，SIRT5是一种多功能酶，可调节线粒体和细胞质中的重要代谢途径。在这些细胞中，SIRT5敲低导致生长抑制和细胞死亡，而正常的健康骨髓细胞不受影响。我们建议使用SIRT5敲低和代谢分析来确定AML干细胞中的其他关键存活途径，以便用小分子利用这些途径。这些数据将与体细胞突变筛选，基因表达分析和代谢组学分析相关，以了解SIRT5依赖性的机械基础。我们的研究有可能建立原则证明SIRT5是AML的治疗靶标，为开发临床上的VIABL SIRT5抑制剂的发展提供了科学原理，以治疗AML以及可能其他类型的癌症。重要的是，SIRT5缺失的小鼠是可行的，并且没有主要缺陷，这表明SIRT5抑制剂将得到很好的耐受性。