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.

项目摘要/摘要 急性髓样白血病（AML）是一种遗传复杂且异质的疾病，其特征是 多种突变集。尽管许多患者最初对治疗有反应，但许多患者最终会复发。在 最近十年，AML中对遗传多样性和克隆等级的欣赏为新颖 特定AML亚型的治疗靶标和治疗方法。而且，已经发现AML 具有独特的代谢特征，具有治疗意义。最重要的是，酶的突变 异氯酸酯脱氢酶（IDH1/2）已导致临床认可的药物。但是，许多患者成为 对此疗法也有抵抗力，进一步强调了对靶向失调的新策略的需求 白血病的代谢。通过开发新型的微型机油平台来探索白血病代谢 随着HP MR（Jeong等人，科学进步2017），我们已经确定了新的代谢脆弱性 白血病的糖酵解代谢（Jeong et al。细胞代谢2021）。这种对糖酵解代谢的依赖 不仅改变葡萄糖通量到乳酸，还改变了丝氨酸途径的一碳通量，从而促进 谷氨酰胺的代谢。此外，我们发现遗传靶向或药理抑制 通过该途径（PHGDH）介导通量的酶使这些细胞中的新脆弱性大大化了。 重要的是，该靶向不会影响正常的造血细胞生长。因此，建立在广泛的基础上 我们的实验室与充足的初步数据之间的合作，我们旨在采用创新的方法来学习 代谢（Keshari Lab），包括开发非侵入性探针以测量糖酵解和 超极化磁共振成像的氧化应激。这种新陈代谢将以良好为特征 具有遗传和药理调节的AML（Kharas Lab）的定义模型，以发展 评估白血病 - 茎细胞驱动的AML代谢和抑制丝氨酸代谢的策略。 总之，这些研究将导致新的机械见解和新型的癌症疗法。