Therapeutic Targeting of Human AML Stem Cells

人类 AML 干细胞的治疗靶向

• 批准号: 10256748
• 负责人: Craig T. Jordan
• 金额: $ 93.13万
• 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/10256748
• 关键词: Acute Myelocytic Leukemia; Applications Grants; BCL2 gene; Biological; Clinical Research; Development; Disease; Epigenetic Process; Foundations; Genetic; Goals; Heterogeneity; Human; Intervention; Metabolic; Newly Diagnosed; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Plant Roots; Property; Regimen; Relapse; Therapeutic; Translations; Work; design; improved; improved outcome; inhibitor/antagonist; 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.

总结 该提案的重点是开发急性髓细胞白血病（AML）的改进疗法。 我们所有工作的中心前提是AML是由一种生物学上不同的白血病干细胞驱动的 (LSC)人口虽然从根本上针对白血病的概念重要性是明确的， 近年来的研究表明，LSC固有的患者内异质性 因此，对于大多数患者来说，完全根除是一个非常具有挑战性的目标。我们的研究 因此，他们试图鉴定原代人LSC的共同基础性质， 用于治疗策略的开发，希望内在异质性可以 克服特别令人感兴趣的是，我们已经描述了LSC中不同的代谢特性， 新的干预机会。具体地，BCL 2的抑制作用是抑制氧化应激。 LSC中的磷酸化，导致LSC群体的选择性根除。最新翻译 临床研究的这一观察结果已证明对新诊断的AML具有很强的疗效 病人，似乎正在改变目前的护理标准。尽管这些令人兴奋的 尽管取得了进展，但复发仍然很常见，进一步阐明LSC的性质是必要的。到 为此，我们最近开始描述驱动AML患者复发的机制 在用BCL 2抑制剂治疗之后。这些研究发现了完全出乎意料的新的 LSC生物学的各个方面对我们对AML的基本理解也有重要影响， 作为改进治疗方案的设计。具体来说，我们已经证明，至少有两个 不同的LSC群体可以在同一患者中共存。遗传、表观遗传和代谢 共同居住的LSC亚群的性质可能不同，导致不同水平的药物 响应能力。我们未来研究的重点将是理解和利用这些发现 以改善AML患者的预后为目标。