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) 被认为是在早期造血干细胞或祖细胞出现异常时出现的 细胞获得突变，导致白血病干细胞（LSC）的发育。未能充分 使用常规化疗根除 LSC 会导致疾病进展，并且 复发是 AML 死亡的主要原因。因此，更有效的策略 根除 LSC 具有非常重要的潜力，可以解决紧迫的未满足的临床问题 需要。 最近的临床研究使用 BCL-2 抑制剂 Venetoclax 与阿扎胞苷的组合 (ven/aza) 对老年 AML 患者显示出显着的效果，频率很高 深度且持久的完全缓解。这些结果表明该方案的目标是 体内LSC群体。我们的实验室研究表明，中心分子 根除 LSC 的机制依赖于氧化磷酸化的抑制 （氧化磷）。具体来说，新诊断患者中的 LSC 利用氨基酸的分解代谢作为 驱动 OXPHOS 的主要燃料。 ven/aza 方案可减少氨基酸代谢，从而 抑制 OXPHOS 并导致 LSC 死亡。然而，一些 AML 患者是难治性的或 获得对 ven/aza 疗法的抵抗力。因此，本提案的目标是阐明 LSC 对 ven/aza 疗法产生耐药性的机制。我们建议在 至少 3 种导致耐药性的机制，每种机制都涉及代谢补偿 避免使用氨基酸代谢作为 OXPHOS 的燃料。我们的研究将 涉及对每种机制的详细分析，目的是确定临床疗法 旨在恢复对 ven/aza 的敏感性和/或 LSC 所需的目标代谢机制 生存。