Metabolic mechanisms of venetoclax resistance in acute myeloid leukemia stem cells

急性髓系白血病干细胞维奈托克耐药的代谢机制

• 批准号: 9913861
• 负责人: Craig T. Jordan
• 金额: $ 36.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913861
• 关键词: Acute Myelocytic Leukemia; Address; Amino Acids; Applications Grants; Automobile Driving; Azacitidine; BCL2 gene; Bypass; Catabolism; Cause of Death; Cell Death; Cell Survival; Cellular Metabolic Process; Citric Acid Cycle; Clinical; Clinical Research; Data; Development; Disease; Disease Progression; Disease remission; Drug resistance; Elderly Acute Myeloblastic Leukemia; Energy Metabolism; Failure; Fatty Acids; Financial compensation; Frequencies; Goals; Heel; Hematopoietic stem cells; Laboratory Study; MCL1 gene; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mutation; Newly Diagnosed; Niacinamide; Outcome; Oxidative Phosphorylation; PTPN11 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Refractory; Regimen; Relapse; Resistance; Therapeutic; Up-Regulation; amino acid metabolism; base; chemotherapy; cytotoxic; fatty acid metabolism; fatty acid oxidation; improved; in vivo; inhibitor/antagonist; leukemia treatment; leukemic stem cell; mutant; novel therapeutics; patient population; patient subsets; resistance mechanism; response; stem cell population; stem cells; therapy design

Acute myeloid leukemia (AML) is thought to arise when early hematopoietic stem or progenitor cells acquire mutations leading to the development of leukemia stem cells (LSCs). Failure to fully eradicate LSCs using conventional chemotherapy is responsible for disease progression and relapse, which is the main cause of death in AML. Therefore, strategies that more effectively eradicate LSCs have the potential to be highly significant and to address an urgent unmet clinical need. Recent clinical studies using a combination of the BCL-2 inhibitor venetoclax with azacitidine (ven/aza) have demonstrated remarkable results for elderly AML patients, with a high frequency of deep and durable complete remissions. These outcomes suggest that the regimen is targeting the LSC population in vivo. Our laboratory studies have shown that the central molecular mechanism driving eradication of LSCs relies upon inhibition of oxidative phosphorylation (OXPHOS). Specifically, LSCs in newly diagnosed patients utilize catabolism of amino acids as the primary fuel to drive OXPHOS. The ven/aza regimen reduces amino acid metabolism, thereby inhibiting OXPHOS and leading to LSC death. However, some AML patients are refractory or acquire resistance to the ven/aza regimen. Thus, the goal of this proposal is to elucidate the mechanisms by which LSCs become resistant to ven/aza therapy. We propose that there are at least 3 mechanisms leading to drug resistance, each involving metabolic compensation that circumvents the use of amino acid metabolism as a means to fuel OXPHOS. Our studies will involve detailed analysis of each mechanism, with the objective of defining clinical therapies designed to restore sensitivity to ven/aza and/or to target metabolic mechanisms required for LSC survival.

急性髓系白血病（AML）被认为是由早期造血干细胞或祖细胞 细胞获得导致白血病干细胞（LSC）发育的突变。未能充分 使用常规化疗根除LSC是疾病进展的原因， 复发，这是AML死亡的主要原因。因此，更有效的战略 根除LSC有可能非常重要，并解决紧急的未满足的临床需求。 需要的 BCL-2抑制剂venetoclax与阿扎胞苷联合应用的近期临床研究 (ven/aza）在老年AML患者中表现出显著的效果， 深度持久的完全缓解这些结果表明，该方案是针对 体内LSC群体。我们的实验室研究表明， 驱动LSC根除的机制依赖于氧化磷酸化的抑制 （OXPHOS）。具体地，新诊断患者中的LSC利用氨基酸的催化剂作为 驱动奥克斯福的主要燃料Ven/aza方案降低氨基酸代谢，从而 抑制OXPHOS并导致LSC死亡。然而，一些AML患者是难治性的， 获得对Ven/aza方案的耐药性。因此，本提案的目的是阐明 LSC对ven/aza疗法产生抗性的机制。我们建议， 至少有3种机制导致耐药性，每种机制都涉及代谢补偿， 避免使用氨基酸代谢作为一种手段，以燃料OXPHOS。我们的研究将 涉及每种机制的详细分析，目的是确定临床治疗方法 旨在恢复对ven/aza和/或LSC所需的靶向代谢机制的敏感性 生存