Therapeutic Targeting of MDS Stem Cells

MDS 干细胞的治疗靶向

基本信息

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
项目类别：
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

项目摘要

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) 干细胞的特性细胞将导致MDS治疗靶向策略的改进，恶性干细胞被认为是疾病的核心，推动疾病的进展和最终转化为急性髓系白血病（AML），而某些药物具有抗白血病活性。 MDS，很少有临床批准的药物能够有效消除 MDS 干细胞。因此，我们的研究重点关注细胞代谢的基本方面作为潜在的开发新疗法的切入点已经变得越来越清楚。造血干细胞 (HSC) 表现出独特的代谢特性，使其与造血干细胞区分开来。我们认为 MDS 干细胞也同样独特。并采用不同于大量MDS细胞以及正常细胞的代谢机制事实上，我们的初步数据表明，与正常 HSC 一样，大多数 MDS 都是如此。干细胞处于静止状态，处于活性氧相对较低的状态（称为但有趣的是，MDS 干细胞在发病过程中会转变为能量。以优先依赖氧化磷酸化为特征的代谢表型。在同一过渡阶段，MDS 干细胞也强烈上调蛋白质合成这些独特的生物学特性使得 MDS 干细胞易于接受治疗。事实上，我们的临床前模型研究已经证实了 Venetoclax 和 omacetaxine 等药物的作用。这些药物非常成功，以至于开发了两项新的临床试验来测试这两项试验最近开始，目前正在进行中。我们打算对接受治疗的患者的 MDS 干细胞进行详细分析我们还将进行进一步的临床前建模，以更好地表征这些试验。除了高风险之外，MDS干细胞可以被选择性根除的机制。疾病阶段，我们的研究将扩大到包括低风险和中风险的患者综上所述，拟议的研究将阐明 MDS 的关键代谢途径。介导 MDS 干细胞的存活并确定治疗 MDS 患者的新策略。