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.

概括 该提案的重点是开发针对急性髓系白血病（AML）的改进疗法。 我们所有工作的核心前提是 AML 是由生物学上独特的白血病干细胞驱动的 （LSC）人口。虽然从根源上打击白血病的概念重要性是显而易见的， 近年来的研究表明，LSC 固有的患者内部异质性 对于大多数患者来说，彻底根除这一疾病是一个非常具有挑战性的目标。我们的研究 因此，我们试图确定原代人类 LSC 的共同基本特性，这些特性可以 用于制定治疗策略，希望能够消除内在的异质性 克服。特别有趣的是，我们描述了 LSC 中独特的代谢特性，这些特性提供了 干预的新机会。具体来说，抑制 BCL2 可抑制氧化 LSC 中的磷酸化，导致 LSC 群体的选择性根除。最近翻译 这一观察到的临床研究已证明对新诊断的 AML 具有强大的疗效 患者，并且似乎即将改变当前的护理标准。尽管有这些激动人心的 尽管取得了进展，但复发仍然很常见，进一步阐明 LSC 特性至关重要。到 为此，我们最近开始描述导致 AML 患者复发的机制 使用 BCL2 抑制剂治疗后。这些研究发现了完全意想不到的新的 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 共存 LSC 亚群的特性可能会有所不同，从而产生不同水平的药物 反应能力。我们未来研究的重点将是理解和利用这些发现 旨在改善 AML 患者的治疗结果。