Characterization and targeting of leukemia stem cell metabolism

白血病干细胞代谢的表征和靶向

• 批准号: 9305948
• 负责人: Craig T. Jordan
• 金额: $ 49.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305948
• 关键词: 5' -AMP-activated protein kinase; Activities of Daily Living; Acute Myelocytic Leukemia; Applications Grants; Automobile Driving; Biochemical; Biological; Biology; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Data; Development; Disease; Disease Progression; Drug resistance; Drug usage; Energy Metabolism; Failure; Genetic; Genetic study; Glycolysis; Goals; Growth; Heart Diseases; Hematopoietic System; Hematopoietic stem cells; Human; In Vitro; Lead; Maintenance; Measures; Metabolic; Metabolic Pathway; Metabolism; Molecular; NADP; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology Study; Phosphotransferases; Population; Pre-Clinical Model; Process; Production; Property; Protein Kinase; Protein Kinase Inhibitors; Reactive Oxygen Species; Reagent; Regimen; Regulation; Relapse; Role; Series; Specimen; Stem cells; Testing; Therapeutic; Therapeutic Agents; Tumor Biology; Work; Xenograft Model; analog; base; cell type; design; drug discovery; fatty acid oxidation; fitness; improved; leukemic stem cell; metabolomics; neoplastic cell; novel strategies; novel therapeutics; primitive cell; protein kinase inhibitor; sensor; small molecule inhibitor; stem; theories; therapeutic candidate; therapeutic target

Project Summary The goal of this application is to elucidate properties of human leukemia stem cells (LSCs) that will lead to improved strategies for therapeutic targeting. Specifically, in the context of acute myelogenous leukemia (AML), LSCs are thought to reside at the heart of disease, driving progression and relapse. While many drugs have activity in AML, few if any clinically approved agents are known to efficiency eradicate LSCs. Thus, our studies have focused on the fundamental property of energy metabolism as a potential entry point for developing novel therapies. It has become increasingly clear that normal hematopoietic stem cells (HSCs) display unique metabolic properties that distinguish them from other cells in the hematopoietic system. We propose that AML stem cells will be similarly unique and employ metabolic mechanisms that are distinct from bulk AML cells as well as normal stem/progenitor cells. Indeed, our preliminary data show that like normal HSCs, most LSCs reside in a state of relatively low reactive oxygen species (termed “ROS-low”). Further, we show that the metabolic sensor AMPK is preferentially activated in the ROS-low LSC population, and is responsible for modulating energy metabolism as reflected in the use of fatty acid oxidation as well as steady- state levels of NADPH. Importantly, genetic inhibition of AMPK is sufficient to dramatically reduce the functional ability of LSCs. These data lead us to hypothesize that LSCs preferentially reside in a distinct metabolic condition characterized by a ROS-low status and activation of AMPK. Further, we propose that modulation of AMPK (and related pathways) can be employed to “push” LSCs out of the ROS-low state, thereby reducing their fitness and/or rendering them more susceptible to targeting by available therapeutic agents. To test these theories, we will perform a detailed metabolomic analysis of primary human AML specimens in order to examine relative utilization of energy pathways in primitive cell types. These studies will focus in particular on the role of AMPK. We will also perform drug discovery/development studies to create improved small molecule inhibitors of AMPK. Taken together, the proposed studies will elucidate the key metabolic pathways that control energy metabolism in LSCs and identify novel strategies for therapeutic targeting of the LSC population.

项目概要 此应用的目标是阐明人类白血病干细胞 (LSC) 的特性： 将导致治疗靶向策略的改进。具体来说，在严重的情况下 骨髓性白血病 (AML) 中，LSC 被认为是疾病的核心，导致 进展和复发。虽然许多药物具有治疗 AML 的活性，但很少有药物获得临床批准 已知药剂可以有效根除 LSC。因此，我们的研究重点是 能量代谢的基本特性作为开发新产品的潜在切入点 疗法。越来越清楚的是，正常造血干细胞（HSC） 显示出独特的代谢特性，将其与造血细胞中的其他细胞区分开来 系统。我们认为 AML 干细胞将同样独特并采用代谢 与大量 AML 细胞以及正常干/祖细胞不同的机制。 事实上，我们的初步数据表明，与正常的 HSC 一样，大多数 LSC 都处于 活性氧相对较低（称为“ROS-low”）。此外，我们还表明代谢 传感器 AMPK 在 ROS 低的 LSC 群体中优先激活，并负责 调节能量代谢，反映在脂肪酸氧化的使用以及稳定 NADPH 的州水平。重要的是，AMPK 的基因抑制足以显着 降低LSC的功能。这些数据使我们推测 LSC 优先处于以 ROS 低状态为特征的独特代谢条件下 AMPK 的激活。此外，我们建议 AMPK（和相关途径）的调节可以 用于“推动”LSC 脱离 ROS 低状态，从而降低其适应度和/或 使它们更容易被可用的治疗剂靶向。为了测试这些 理论上，我们将对原发性人类 AML 标本进行详细的代谢组学分析 为了检查原始细胞类型中能量途径的相对利用。这些研究 将特别关注 AMPK 的作用。我们还将进行药物发现/开发 研究创造改进的 AMPK 小分子抑制剂。综合起来，建议 研究将阐明控制 LSC 能量代谢的关键代谢途径 确定针对 LSC 群体的治疗目标的新策略。