Metabolic targeting of heterogenous myelodysplastic syndrome stem cells

异源性骨髓增生异常综合征干细胞的代谢靶向

• 批准号: 10788983
• 负责人: Eric M Pietras
• 金额: $ 42.24万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10788983
• 关键词: Address; Aftercare; Automobile Driving; Azacitidine; Behavior; Biological; Biological Assay; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clinical Trials; Clone Cells; Coupled; Data; Disease; Disease Progression; Dose Limiting; Dysmyelopoietic Syndromes; Foundations; Genotype; Goals; Hematopoietic stem cells; Heterogeneity; Hydrogenase; In complete remission; Individual; Laboratories; Laboratory Study; Link; Metabolic; Modality; Modeling; Molecular; Molecular Genetics; Myelogenous; Niacinamide; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Proliferating; Property; Protein Biosynthesis; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Proteins; Recurrent disease; Regimen; Research Personnel; Residual Neoplasm; Resistance; Resolution; STAT3 gene; Safety; Signal Pathway; Specimen; Therapeutic; Toxic effect; Translational Repression; Translations; Vertebral column; Work; cancer stem cell; cohort; design; genetic approach; high risk; improved; improved outcome; in vivo; inhibitor; mortality; next generation; novel strategies; novel therapeutic intervention; novel therapeutics; patient subsets; pharmacologic; rational design; response; standard of care; stem cell population; stem cells; treatment response

PROJECT SUMMARY/ABSTRACT The goal of this project is to define vulnerabilities that can be leveraged to comprehensively eradicate MDS stem cells (MDS-SCs). This objective is based on the concept that MDS-SCs lie at the root of disease and are not effectively targeted by current therapies. A significant challenge in achieving this goal is the heterogeneity of the MDS-SC population, as recent studies have identified distinct subsets of MDS-SC with varying responsiveness to therapy. Thus, the premise of our work is that understanding and targeting the unique properties of heterogenous MDS-SCs is critical to improve outcomes in MDS. The foundation of our project is built upon laboratory studies coupled with an active clinical trial (NCT03564873) evaluating the clinical impact of targeting protein synthesis with the global translation inhibitor omacetaxine (oma) in MDS-SC from individuals with high- risk MDS. While the results from our trial using oma in combination with the hypomethylating agent azacytidine (aza) are indeed promising and represent a substantial improvement over standard of care (aza alone), instances of disease progression in patients suggest oma may not eradicate all MDS-SC subsets. These outcomes, alongside toxicities associated with global protein translation inhibition have motivated us to better characterize the unique biological and functional properties of heterogenous MDS-SC subsets. With the goal of developing next-generation approaches that more effectively target MDS-SC while minimizing dose-limiting toxicities to patients, here we will address two primary questions: 1) what is the overall efficacy of protein synthesis inhibition amongst varying MDS-SC subtypes, 2) what are the optimal therapeutic strategies to eradicate MDS-SC based on their sensitivity to protein synthesis inhibition? Hence, we will leverage comprehensive CITE-seq based analyses of serial pre- and post-treatment specimens from our oma/aza clinical trial alongside PDX-based functional studies to identify the link(s) between features such as protein synthesis activity, MDS-SC genotype and clonal behavior with oma response at single cell resolution. We will define the mechanisms governing reliance on protein synthesis in MDS-SC, focusing on pharmacological and molecular genetic-based targeting of key pathways linked with oma sensitivity. Lastly, we will develop improved approaches to comprehensively target heterogenous MDS-SC populations, with focus on next-generation strategies that more selectively target aberrant metabolic features of MDS-SC uncovered by our ongoing CITE-seq characterization of patient specimens. Taken together, the proposed studies will use advanced functional models and single-cell resolution analyses to identify key vulnerabilities of MDS-SC that can be leveraged to design rational therapeutic approaches to improve outcomes for MDS patients.

项目总结/摘要 该项目的目标是确定可用于全面根除MDS干细胞的漏洞 细胞（MDS-SC）。这一目标是基于MDS-SC是疾病根源而不是疾病根源的概念。 目前的治疗有效靶向。实现这一目标的一个重大挑战是 MDS-SC人群，因为最近的研究已经确定了具有不同反应性的MDS-SC的不同子集 接受治疗因此，我们工作的前提是，理解和针对的独特性质， 异源MDS-SC对于改善MDS的结果至关重要。我们项目的基础是 实验室研究结合一项评价靶向治疗临床影响的积极临床试验（NCT 03564873） 蛋白质合成与全球翻译抑制剂omacetaxine（oma）在MDS-SC从个人高， 风险MDS。虽然我们使用oma和低甲基化剂氮杂胞苷的试验结果 (aza)确实是有希望的，并且代表了对护理标准（单独使用aza）的实质性改进， 患者的疾病进展表明，瘤可能不会根除所有MDS-SC亚群。这些成果， 与全球蛋白质翻译抑制相关的毒性促使我们更好地表征 异源MDS-SC亚群的独特生物学和功能特性。目标是开发 下一代方法，更有效地靶向MDS-SC，同时最大限度地减少剂量限制性毒性， 在这里，我们将解决两个主要问题：1）蛋白质合成抑制的总体疗效如何 在不同的MDS-SC亚型中，2）根除MDS-SC的最佳治疗策略是什么？ 对蛋白质合成抑制的敏感性因此，我们将利用全面的基于CITE-seq的 对我们的oma/aza临床试验中治疗前和治疗后的系列标本以及基于PDX的 功能研究，以确定蛋白质合成活性、MDS-SC基因型等特征之间的联系 以及在单细胞分辨率下具有OMA应答的克隆行为。我们将定义管理 依赖MDS-SC中的蛋白质合成，专注于基于药理学和分子遗传学的靶向 与肿瘤敏感性相关的关键通路。最后，我们将制定更好的方法， 针对异质性MDS-SC人群，重点关注更有选择性地针对 我们正在进行的患者CITE-seq表征揭示了MDS-SC的异常代谢特征 标本总之，拟议的研究将使用先进的功能模型和单细胞分辨率 分析以识别MDS-SC的关键漏洞，可用于设计合理的治疗方法 改善MDS患者预后的方法。