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

• 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
• 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

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.

项目总结/文摘