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.

项目摘要/摘要 该项目的目标是定义可用于全面根除MDS茎的漏洞 细胞(MDS-SCs)。这一目标是基于以下概念：MDS-SCs是疾病的根源，而不是 有效地被目前的治疗方法所针对。实现这一目标的一个重大挑战是 MDS-SC群体，因为最近的研究发现MDS-SC的不同亚群具有不同的反应性 去接受治疗。因此，我们工作的前提是理解和瞄准 异种MDS-SCs是改善MDS预后的关键。我们项目的基础是建立在 实验室研究结合积极的临床试验(NCT03564873)评估靶向的临床影响 在MDS-SC中用全局翻译抑制剂奥乙酰克辛(OMA)合成蛋白质 风险MDS。而我们将OMA与去甲基化药物氮胞苷联合使用的试验结果 (Aza)确实很有希望，并且比护理标准(仅Aza)有了实质性的改进，例如 患者的疾病进展情况表明，OMA可能不会根除所有MDS-SC亚群。这些结果， 除了与全球蛋白质翻译抑制相关的毒性外，还促使我们更好地表征 异源MDS-SC亚群独特的生物学和功能特性。以发展为目标 更有效地针对MDS-SC的下一代方法，同时将剂量限制毒性降至最低 病人们，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效果是什么 在不同的MDS-SC亚型中，2)根除MDS-SC的最佳治疗策略是什么 关于它们对蛋白质合成抑制的敏感性？因此，我们将利用基于CITE-SEQ的全面 我们的OMA/Aza临床试验与PDX为基础的系列治疗前后样本的分析 功能研究确定蛋白质合成活性、MDS-SC基因型等特征之间的联系(S) 以及在单细胞分辨率下具有OMA响应的克隆行为。我们将定义管理的机制 MDS-SC对蛋白质合成的依赖，侧重于药理学和基于分子遗传的靶向 与OMA敏感性相关的关键通路。最后，我们将制定改进的方法，全面 以异种MDS-SC群体为目标，重点关注更有选择性地针对目标的下一代战略 我们正在进行的患者CITE-SEQ特征揭示了MDS-SC的异常代谢特征 标本。总而言之，拟议的研究将使用先进的功能模型和单细胞分辨率 分析以确定MDS-SC的关键漏洞，可用于设计合理的治疗方案 改善MDS患者预后的方法。