Therapeutic Targeting of MDS Stem Cells

MDS 干细胞的治疗靶向

• 批准号: 10045509
• 负责人: Craig T. Jordan
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045509
• 关键词: Acute Myelocytic Leukemia; Aftercare; Age; Aging; Automobile Driving; Azacitidine; Biologic Characteristic; Biological; Biology; Cell Count; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Data; Development; Diagnostic; Disease; Dysmyelopoietic Syndromes; Dysplasia; Energy Metabolism; Environmental Exposure; Exposure to; Foundations; Future; Generations; Goals; Grant; Heart Diseases; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; IL3RA gene; Ineffective Hematopoiesis; Laboratory Research; Laboratory Study; Marrow; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morbidity - disease rate; Morphology; Myelogenous; Myeloproliferative disease; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase Transition; Phenotype; Poison; Population; Pre-Clinical Model; Preclinical Testing; Property; Protein Biosynthesis; Reactive Oxygen Species; Regimen; Research; Resolution; Risk; Sampling; Study models; Surface Antigens; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Up-Regulation; Veterans; base; cancer stem cell; cytopenia; design; high risk; improved; in vivo; insight; military veteran; novel strategies; novel therapeutic intervention; novel therapeutics; preclinical study; prognostic tool; protein expression; response; single cell technology; single-cell RNA sequencing; stem; stem cell population; stem cell therapy; stem cells; targeted treatment; therapeutic target; therapy development; therapy resistant; treatment strategy

The goal of this application is to elucidate properties of myelodysplastic syndrome (MDS) stem cells that will lead to improved strategies for therapeutic targeting. In the context of MDS, malignant stem cells are thought to reside at the heart of disease, driving progression and ultimately transformation to acute myeloid leukemia (AML). While some drugs have activity in MDS, few if any clinically approved agents are known to efficiency eradicate MDS stem cells. Thus, our studies have focused on fundamental aspects of cellular 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 MDS stem cells are similarly unique and employ metabolic mechanisms that are distinct from bulk MDS cells as well as normal stem/progenitor cells. Indeed, our preliminary data show that like normal HSCs, most MDS stem cells are quiescent and reside in a state of relatively low reactive oxygen species (termed “ROS-low”). Intriguingly though, during pathogenesis MDS stem cells shift to an energy metabolism phenotype characterized by preferential reliance on oxidative phosphorylation. During the same transitional phase, MDS stem cells also strongly up-regulated protein synthesis pathways. These distinct biological properties render MDS stem cells susceptible to therapeutic agents such as venetoclax and omacetaxine. Indeed, our preclinical modeling studies have been so successful with these agents that two new clinical trials have been developed to test their use for high-risk MDS. Both trials recently opened and are now accruing. For the current proposal we intend to perform a detailed analysis of MDS stem cells in the patients treated from these trials. We will also conduct further preclinical modeling to better characterize the mechanism by which MDS stem cells can be selectively eradicated. In addition to high-risk stages of disease, our studies will be extended to include patients with low and intermediate risk MDS. Taken together, the proposed research will elucidate the key metabolic pathways that mediate survival of MDS stem cells and identify novel strategies for treatment of MDS patients.

该应用的目的是阐明骨髓增生综合征（MDS）茎的特性 细胞将改善治疗靶向的策略。在MD的背景下 恶性干细胞被认为位于疾病的核心，驱动进展和 最终转化为急性髓样白血病（AML）。虽然有些药物有活性 MDS，众所周知，没有任何临床批准的药物是效率放射素MDS干细胞。 这是我们的研究集中于细胞代谢的基本方面 开发新疗法的切入点。越来越清楚的是正常 造血干细胞（HSC）表现出独特的代谢特性，可将其与众不同 造血系统中的其他细胞。我们建议MDS干细胞同样独特 和员工代谢机制不同于大量MDS细胞以及正常 茎/祖细胞。确实，我们的初步数据表明，与普通HSC一样，大多数MD 干细胞静止，驻留在相对较低的活性氧（称为）的状态（称为） “ ros-low”）。然而，有趣的是，在发病机理中，MDS干细胞转移到能量 代谢表型的特征是对氧化磷酸化的首选提醒。 在同一过渡阶段，MDS干细胞也强烈上调蛋白质合成 途径。这些不同的生物学特性使MDS干细胞易受治疗 诸如Venetoclax和Omacetaxine之类的药物。确实，我们的临床前建模研究已经 这些药物是如此成功，以至于开发了两项新的临床试验以测试 它们用于高危MD。两项试验最近都开放，现在正在累积。对于电流 提案我们打算在接受治疗的患者中对MDS干细胞进行详细分析 这些试验。我们还将进行进一步的临床前建模，以更好地表征 MDS干细胞可以选择性地放射线的机制。除了高风险 疾病阶段，我们的研究将扩展到包括低风险和中等风险的患者 MDS。综上所述，拟议的研究将阐明 介导MDS干细胞的存活率，并确定治疗MDS患者的新型策略。