Therapeutic Targeting of MDS Stem Cells

MDS 干细胞的治疗靶向

• 批准号: 10618854
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618854
• 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; 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; Phenotype; Poison; Population; Pre-Clinical Model; Preclinical Testing; Predisposition; Property; Protein Biosynthesis; Reactive Oxygen Species; Regimen; Research; Resolution; Risk; Sampling; Study models; Surface Antigens; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Up-Regulation; Veterans; cancer stem cell; cytopenia; design; diagnostic tool; efficacy evaluation; high risk; improved; in vivo; insight; military veteran; novel strategies; novel therapeutic intervention; novel therapeutics; preclinical study; prognostic tool; progression risk; protein expression; response; single cell technology; single-cell RNA sequencing; 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.

本申请的目的是阐明骨髓增生异常综合征（MDS）干细胞的特性 这些细胞将导致改进的治疗靶向策略。在MDS的背景下， 恶性干细胞被认为是疾病的核心，推动疾病的进展， 最终转化为急性髓性白血病（AML）。虽然有些药物在体内具有活性， 在MDS中，已知很少（如果有的话）临床上批准的药剂有效根除MDS干细胞。 因此，我们的研究集中在细胞代谢的基本方面， 开发新疗法的切入点。越来越明显的是， 造血干细胞（HSC）显示出独特的代谢特性， 造血系统中的其他细胞。我们认为，MDS干细胞是类似独特的， 并采用不同于大量MDS细胞以及正常MDS细胞的代谢机制， 干/祖细胞。事实上，我们的初步数据表明，像正常的HSC，大多数MDS， 干细胞是静止的，并处于相对低活性氧物质的状态（称为 “ROS-低”）。有趣的是，在发病过程中，MDS干细胞转变为一种能量 以优先依赖氧化磷酸化为特征的代谢表型。 在同一过渡期，MDS干细胞也强烈上调蛋白质合成 途径。这些独特的生物学特性使得MDS干细胞对治疗敏感。 药物如维奈托克和奥美他辛。事实上，我们的临床前建模研究 这些药物如此成功，以至于已经开发了两项新的临床试验来测试 用于高风险MDS。这两项审判最近开始，目前正在进行中。为当前 我们打算对接受治疗的患者的MDS干细胞进行详细分析， 这些审判。我们还将进行进一步的临床前建模，以更好地表征 MDS干细胞可以被选择性地根除的机制。除了高风险 疾病的阶段，我们的研究将扩大到包括低风险和中等风险的患者 MDS总之，拟议的研究将阐明关键的代谢途径， 介导MDS干细胞的存活，并确定治疗MDS患者的新策略。