Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia

靶向急性髓系白血病的代谢调节因子 SIRT5

• 批准号: 10670103
• 负责人: Michael W. Deininger
• 金额: $ 36.99万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670103
• 关键词: Acute Myelocytic Leukemia; Allogenic; Apoptosis; Attenuated; BCL2 gene; Biochemical; Biological Availability; Biology; Bone Marrow; CD34 gene; CRISPR/Cas technology; Catabolism; Cell Death; Cell Line; Cell Survival; Cells; Clinical; Data; Dependence; Development; Drug Targeting; Energy Metabolism; Enzymes; Equilibrium; Exhibits; FLT3 gene; FLT3 inhibitor; Fatty Acids; Future; Gene Expression Profile; Genes; Genetic; Genotype; Glutamine; Glycolysis; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell subsets; Hematopoietic stem cells; Homeostasis; Impairment; In Vitro; In complete remission; Isocitrate Dehydrogenase; Knock-out; Lead; Leukemic Cell; Leukocytes; Lysine; MLL-AF9; Malignant - descriptor; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Minor; Mitochondria; Mus; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Oncogenes; Organ; Oxidation-Reduction; Oxidative Phosphorylation; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prognosis; Proliferating; Reagent; Reduced Glutathione; Regulation; Relapse; Resistance development; Role; Sampling; Sirtuins; Solid Neoplasm; Somatic Mutation; Stem cell transplant; Stress; Superoxides; Testing; Therapeutic; Validation; Work; acute myeloid leukemia cell; biomarker identification; branched-chain-amino-acid transaminase; cancer cell; chemotherapy; clinical development; exome sequencing; experience; flexibility; in vivo; inhibitor; knock-down; leukemia; leukemia initiating cell; leukemia treatment; leukemogenesis; meter; mitochondrial metabolism; mouse model; mutant; nanomolar; new therapeutic target; novel; novel therapeutics; oxidation; relapse patients; resistance mutation; response; scaffold; segregation; small hairpin RNA; stable isotope; stem; stem cells; targeted treatment; tool; transcriptome sequencing; tumor heterogeneity

PROJECT SUMMARY TARGETING THE METABOLIC REGULATOR SIRT5 IN ACUTE MYELOID LEUKEMIA. AML is an aggressive hematologic malignancy with <30% long-term survival. The current therapy standard, chemotherapy alone or combined with allogeneic stem cell transplant, has not changed for decades. Despite initial responses, most patients eventually relapse, suggesting persistence of leukemia initiating cells in protective niches. Inhibitors of FLT3 or mutant isocitrate dehydrogenase 1/2 (IDH1/2) have expanded therapy options and validated the paradigm of genotype-directed therapy. However, even with these new drugs, relapse is common and frequently due to selection of subclones with resistance mutations in the drug target. Unlike FLT3 and IDH1/2 inhibitors, the BCL2 inhibitor venetoclax is active in multiple AML genotypes, indicating that targeting shared vulnerabilities in a genotype-agnostic manner can be effective. Unfortunately many venetoclax-induced responses are not durable as leukemia cells adapt by activating alternative anti-apoptosis mechanisms or by reprogramming mitochondrial metabolism. Microenvironmental protection, intra-tumoral heterogeneity and metabolic flexibility limit the utility of current AML therapies. To identify new therapy targets in AML, we adapted an shRNA screen for testing primary AML cells under bone marrow microenvironment-like conditions. We discovered that many AML patient samples are highly dependent on SIRT5, while normal CD34+ cells are not. SIRT5 is a lysine deacylase implicated in the regulation of energy metabolic pathways, including oxidative phosphorylation (OXPHOS), fatty acid β-oxidation and glycolysis. SIRT5 knockdown (KD) reduces growth and increases apoptosis in most AML cell lines, with consistent results upon disruption of SIRT5 using CRISPR/Cas9 or NRD167, a novel cell-permeable SIRT5 inhibitor. Genetic absence of Sirt5 impairs in vitro transformation of mouse hematopoietic cells by several myeloid oncogenes, including MLL-AF9, and attenuates leukemogenesis in vivo. At a biochemical level, SIRT5 KD or inhibition with NRD167 is associated with reduced OXPHOS, reduced glutathione levels and increased mitochondrial superoxide, suggesting that AML cells depend on SIRT5 to maintain redox homeostasis. Sirt5-/- mice are viable with minor metabolic abnormalities, suggesting that in vivo inhibition of SIRT5 would be tolerated. We hypothesize that SIRT5 is a therapy target in AML and will test this in three Specific Aims: (1) Identify and validate SIRT5-regulated metabolic pathways in normal and AML stem and progenitor cells. (2) Identify biomarkers of sensitivity to SIRT5 inhibition in primary AML cells. (3) Identify a potent, selective, and bioavailable SIRT5 inhibitor, starting from the NRD167 tool compound. Our work will rigorously test whether SIRT5 is a therapy target in AML, clarify the mechanisms underlying SIRT5 dependence, and identify potent and selective SIRT5 inhibitors for future clinical development.

项目总结