Interrogation of the oxidative-stress-induced leukemia program in vivo using metabolic imaging

使用代谢成像研究体内氧化应激诱导的白血病程序

基本信息

批准号：
10729140
负责人：
Kayvan R Keshari
金额：
$ 72.81万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729140
关键词：
Acute Myelocytic Leukemia Address Anabolism Automobile Driving Biological Markers Carbohydrates Carbon Cell Compartmentation Cell Line Cells Cellular Metabolic Process Clinical Collaborations Companions Complex Data Dependence Development Diet Disease Environment Enzyme Inhibition Enzymes FLT3 gene Future Genetic Genetic Variation Glucose Glutamine Glycolysis Goals Hematopoietic Heterogeneity Human Image Isocitrate Dehydrogenase Isotopes Knowledge Link Lipids MLL-AF9 Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Metabolic Metabolic Pathway Metabolism Modeling Motivation Mus Mutation Myeloid Leukemia Nutrient Organism Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphoglycerate dehydrogenase Publishing Pyruvate Relapse Research Resistance Role Sampling Science Serine Sorting Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Therapeutic Translating Visualization Work acute myeloid leukemia cell cancer therapy cell growth chemotherapy dehydroascorbate design human cord blood CD34+ cell imaging approach imaging biomarker in vivo individualized medicine innovation insight leukemia leukemic stem cell mass spectrometric imaging metabolic abnormality assessment metabolic imaging new therapeutic target novel novel marker novel strategies novel therapeutic intervention novel therapeutics overexpression pharmacologic programs response stem cell biology stem cells stemness stress state therapeutic development therapy resistant tool treatment planning treatment response tumor metabolism

项目摘要

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by a diverse set of mutations. Although many patients initially respond to treatment, many end up relapsing. Over the last decade, an appreciation of the genetic diversity and clonal hierarchy in AML has opened the door to novel therapeutic targets and therapeutic approaches to specific AML subtypes. Moreover, AML has been found to bear unique metabolic features with therapeutic implications. Most importantly, mutations in the enzymes isocitrate dehydrogenase (IDH1/2) have led to clinically approved drugs. However, many patients become resistant to this therapy as well, further underscoring the need for new strategies to target dysregulated metabolism in leukemia. Through the development of novel microcoil platforms to explore leukemia metabolism with HP MR (Jeong et al. Science Advances 2017) we have identified a new metabolic vulnerability in the glycolytic metabolism of leukemia (Jeong et al. Cell Metabolism 2021). This reliance on glycolytic metabolism alters not only glucose flux to lactate, but also one-carbon flux through the serine pathway, which facilitates the metabolism of glutamine. Moreover, we found that genetically targeting or pharmacologically inhibiting the enzyme that mediates flux through this pathway (PHGDH) capitalizes on a new vulnerability in these cells. Importantly, this targeting does not affect normal hematopoietic cell growth. Thus, building upon extensive collaboration between our labs and ample preliminary data, we aim to employ innovative approaches to study metabolism (Keshari Lab), including by developing non-invasive probes to measure changes in glycolysis and oxidative stress with hyperpolarized magnetic resonance imaging. This metabolism will be characterized in well- defined models of AML (Kharas Lab), with both genetic and pharmacological modulation, in order to develop a strategy to assess leukemia-stem-cell-driven AML metabolism and the inhibition of serine metabolism. Altogether, these studies will result in new mechanistic insights and novel cancer therapies.

项目概要/摘要急性髓系白血病 (AML) 是一组遗传复杂且异质性的疾病，其特征是不同的突变组。尽管许多患者最初对治疗有反应，但许多患者最终会复发。超过过去十年，对 AML 遗传多样性和克隆等级的认识为新的治疗方法打开了大门特定 AML 亚型的治疗靶点和治疗方法。此外，已发现 AML 具有具有治疗意义的独特代谢特征。最重要的是酶的突变异柠檬酸脱氢酶 (IDH1/2) 已导致药物获得临床批准。然而，许多患者却成为也对这种疗法产生抵抗力，进一步强调需要针对失调的新策略白血病的代谢。通过开发新型微线圈平台探索白血病代谢借助 HP MR（Jeong 等人，Science Advances 2017），我们发现了一种新的代谢脆弱性白血病的糖酵解代谢（Jeong et al. Cell Metabolism 2021）。这种对糖酵解代谢的依赖不仅改变葡萄糖流向乳酸，还改变通过丝氨酸途径的一碳流，这有利于谷氨酰胺的代谢。此外，我们发现基因靶向或药理学抑制介导通过该途径的通量的酶（PHGDH）利用了这些细胞中的新脆弱性。重要的是，这种靶向不会影响正常的造血细胞生长。因此，在广泛的基础上我们的实验室之间的合作和充足的初步数据，我们的目标是采用创新的方法来研究新陈代谢（Keshari Lab），包括开发非侵入性探针来测量糖酵解和代谢的变化超极化磁共振成像的氧化应激。这种新陈代谢的特点是定义了 AML 模型（Kharas 实验室），具有遗传和药理调节功能，以便开发评估白血病干细胞驱动的 AML 代谢和丝氨酸代谢抑制的策略。总而言之，这些研究将产生新的机制见解和新的癌症疗法。