Therapeutic Targeting of Human AML Stem Cells

人类 AML 干细胞的治疗靶向

• 批准号: 10681358
• 负责人: Craig T. Jordan
• 金额: $ 89.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681358
• 关键词: Acute Myelocytic Leukemia; Applications Grants; BCL2 gene; Clinical Research; Development; Disease; Epigenetic Process; Genetic; Goals; Heterogeneity; Human; Intervention; Metabolic; Newly Diagnosed; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Property; Regimen; Relapse; Therapeutic; Translations; Work; design; improved; improved outcome; inhibitor; interest; leukemia; leukemic stem cell; standard of care; stem cell biology; stem cell population; therapeutic development; therapeutic target

Summary This proposal is focused on the development of improved therapies for acute myeloid leukemia (AML). The central premise of our all our work is that AML is driven by a biologically distinct leukemia stem cell (LSC) population. While the conceptual importance of targeting leukemic disease at its root is clear, studies in recent years have demonstrated that the inherent intra-patient heterogeneity of LSC populations makes complete eradication a very challenging objective for most patients. Our studies have therefore attempted to identify common foundational properties of primary human LSCs that can employed in the development of therapeutic strategies in the hope that intrinsic heterogeneity can be overcome. Of particular interest, we have described distinct metabolic properties in LSCs, that provide new opportunities for intervention. Specifically, inhibition of BCL2 acts to inhibit oxidative phosphorylation in LSCs, resulting in selective eradication of the LSC population. Recent translation of this observation to clinical studies has demonstrated strong efficacy for newly diagnosed AML patients, and appears to be on the verge of altering the current standard of care. Despite these exciting advances though, relapse remains common and further elucidation of LSC properties is essential. To this end, we have recently begun to describe the mechanisms that drive relapse of AML patients following treatment with a BCL2 inhibitor. These studies have identified entirely unexpected and new aspects of LSC biology that have important ramifications for our basic understanding of AML, as well as the design of improved therapeutic regimens. Specifically, we have demonstrated that at least two distinct LSC populations can co-exist in the same patient. The genetic, epigenetic, and metabolic properties of co-resident LSC subpopulations can vary, giving rise to differing levels of drug responsiveness. The focus of our studies going forward will be to understand and exploit these findings towards the goal of improved outcomes for AML patients.

概括 该建议的重点是开发改进的急性髓样白血病（AML）的疗法。 我们所有工作的中心前提是AML是由生物学上不同的白血病干细胞驱动的 （LSC）人口。虽然将白血病疾病靶向其词根的概念重要性是明确的，但 近年来的研究表明，LSC固有的病毒内异质性 对于大多数患者而言，人口完全消除是一个非常具有挑战性的目标。我们的研究 因此，试图确定原代人LSC的共同基础特性 用于制定治疗策略，希望可以是内在的异质性 克服。我们特别有趣的是，我们描述了LSC中不同的代谢特性 干预的新机会。具体而言，抑制BCL2可起作用以抑制氧化 LSC中的磷酸化，导致LSC种群的选择性消除。最近的翻译 临床研究的这一观察结果表明，新诊断的AML有效 患者，似乎正处于改变当前护理标准的边缘。尽管这些令人兴奋 不过，进步仍然很普遍，LSC特性的进一步阐明至关重要。到 这一目的，我们最近开始描述驱动AML患者复发的机制 用BCL2抑制剂治疗后。这些研究已经确定了完全出乎意料和新的 LSC生物学的各个方面对我们对AML的基本理解具有重要的影响 随着改善治疗方案的设计。具体来说，我们已经证明了至少两个 不同的LSC种群可以在同一患者中共存。遗传，表观遗传和代谢 共同居民LSC亚群的特性可能会有所不同，从而导致药物水平不同 响应能力。未来研究的重点将是理解和利用这些发现 为了改善AML患者的结果。