Metabolic Reprogramming in Brain Tumors

脑肿瘤的代谢重编程

• 批准号: 9204396
• 负责人: Sabrina Miriam Ronen
• 金额: $ 61.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204396
• 关键词: Acute Myelocytic Leukemia; Address; Astrocytes; Biological; Biological Assay; Biological Markers; Biopsy; Brain Neoplasms; Cell Proliferation; Cells; Choline; DNA Methylation; Decarboxylation; Enzymes; Event; Genotype; Glioblastoma; Glioma; Glutamates; Glutaminase; Glutamine; Glutathione; Glycine; Goals; Investigation; Isocitrate Dehydrogenase; Isocitrates; Label; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Monitor; Mutation; Oncogenic; Outcome; Pathway interactions; Patients; Phosphoglycerate dehydrogenase; Production; Quality of life; Regimen; Reporting; Research; Role; Sampling; Stem cells; Taurine; Testing; Therapeutic; Tumorigenicity; Withdrawal; Work; base; brain metabolism; cell immortalization; cell transformation; cellular engineering; genome-wide; histone methylation; imaging biomarker; immortalized cell; in vivo; inhibitor/antagonist; innovation; mutant; novel; novel therapeutic intervention; personalized care; progenitor; public health relevance; pyruvate dehydrogenase; response biomarker; tool; tumor; tumor growth; tumor metabolism; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The goal of this application is to test the hypothesis that the neomorphic activity of mutant isocitrate dehydrogenase (IDH) results not only in production of the oncometabolite 2-hydroxygluatarte (2-HG), but also in a wider metabolic reprogramming which is essential for tumor progression and therefore can be targeted in the treatment of IDH-mutant gliomas. A secondary goal is to identify novel imaging biomarkers for monitoring the normalization of this metabolic reprogramming with treatment. IDH is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to �-ketoglutarate (�-KG). Mutant IDH catalyzes the conversion of �-KG into 2-HG. Mutations in IDH and elevated 2-HG occur in over 70% of gliomas and secondary glioblastomas (GBM) and the IDH mutation is an early event associated with initiation of low grade brain tumors. 1H magnetic resonance spectroscopy (MRS) investigations of patient biopsies performed at UCSF confirmed that 2-HG levels correlate with mutant IDH expression. In addition, several other alterations in steady state metabolite levels were observed. Preliminary studies of cells engineered to express mutant IDH recapitulated the 1H MRS-detectable metabolic changes observed in patient samples and13C MRS confirmed that �-KG is preferentially converted to 2-HG in mutant IDH cells. Furthermore, fluxes via metabolic pathways through which �-KG can be replenished were found to be elevated and inhibition of one such pathway resulted in inhibition of cellular proliferation in mutant IDH cells. These findings form the basis of our hypothesis that mutant IDH leads to a metabolic reprogramming that is essential for mutant IDH tumor growth. We propose to test this hypothesis in a GBM-based model as well as in novel immortalized astrocyte and glial progenitor models via the following aims. Aim 1. To measure flux via specific metabolic pathways in wild-type and mutant IDH cells in order to determine which metabolic pathways are altered by mutant IDH. We will study wild-type and mutant IDH cells and use 13C MRS with 13C-labeled metabolic precursors (hyperpolarized and thermally polarized) as well as 1H MRS and complementary biological methods to probe the metabolic pathways that control the steady state levels of metabolites modulated by mutant IDH. Aim 2. To determine whether the metabolic changes associated with mutant IDH are essential for cell transformation and proliferation. We will modulate the specific metabolic pathways that are altered in mutant IDH cells and determine the consequences of this inhibition on cell proliferation and tumorigenicity. Aim 3. To investigate mutant IDH orthotopic brain tumors in vivo in order to determine the effect of metabolic modulation and to identify MR-based biomarkers of response to metabolic modulation. We will use MRI, 1H and 13C MRS/I as well as complementary biological assays to investigate the effect of inhibiting metabolism on mutant IDH tumor growth and MRS-detectable biomarkers. !

描述（由申请人提供）：本申请的目的是测试这样的假设：突变型异柠檬酸脱氢酶（IDH）的新形态活性不仅导致致癌代谢物2-羟基戊二酸（2-HG）的产生，而且还导致更广泛的代谢重编程，这对于肿瘤进展至关重要，因此可以作为IDH突变型神经胶质瘤的治疗的目标。第二个目标是确定新的成像生物标志物，用于监测治疗后代谢重编程的正常化。 IDH 是催化异柠檬酸氧化脱羧为β-酮戊二酸（β-KG）的酶。突变体 IDH 催化 �-KG 转化为 2-HG。 IDH 突变和 2-HG 升高发生在超过 70% 的神经胶质瘤和继发性胶质母细胞瘤 (GBM) 中，IDH 突变是与低级别脑肿瘤发生相关的早期事件。 UCSF 对患者活检进行的 1H 磁共振波谱 (MRS) 研究证实，2-HG 水平与突变 IDH 表达相关。此外，还观察到稳态代谢水平的其他一些变化。对表达突变 IDH 的细胞进行的初步研究概括了在患者样本中观察到的 1 H MRS 可检测的代谢变化，13 C MRS 证实 �-KG 在突变 IDH 细胞中优先转化为 2-HG。此外，发现通过补充β-KG的代谢途径的通量升高，并且抑制其中一种途径会导致突变IDH细胞的细胞增殖受到抑制。这些发现构成了我们假设的基础，即突变 IDH 会导致代谢重编程，这对于突变 IDH 肿瘤生长至关重要。我们建议通过以下目标在基于 GBM 的模型以及新型永生化星形胶质细胞和神经胶质祖细胞模型中测试这一假设。目标 1. 测量野生型和突变 IDH 细胞中特定代谢途径的通量，以确定突变 IDH 改变了哪些代谢途径。我们将研究野生型和突变型 IDH 细胞，并使用 13C MRS 和 13C 标记的代谢前体（超极化和热极化）以及 1H MRS 和补充生物学方法来探测控制突变 IDH 调节的代谢物稳态水平的代谢途径。目标 2. 确定与突变 IDH 相关的代谢变化是否对细胞转化和增殖至关重要。我们将调节突变 IDH 细胞中改变的特定代谢途径，并确定这种抑制对细胞增殖和致瘤性的影响。目标 3. 研究体内突变型 IDH 原位脑肿瘤，以确定代谢调节的效果并识别代谢调节反应的基于 MR 的生物标志物。我们将使用 MRI、1H 和 13C MRS/I 以及补充生物测定来研究抑制代谢对突变 IDH 肿瘤生长和 MRS 可检测生物标志物的影响。 ！