Metabolic Reprogramming in Brain Tumors

脑肿瘤的代谢重编程

• 批准号: 8613480
• 负责人: Sabrina Miriam Ronen
• 金额: $ 61.73万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613480
• 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; Histones; Image; Inhibition of Cell Proliferation; 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; Patient Care; Patients; Phosphoglycerate dehydrogenase; Production; Quality of life; Regimen; Reporting; Research; Role; Sampling; Stem cells; Taurine; Testing; Therapeutic; Tumorigenicity; Withdrawal; Work; base; cell transformation; cellular engineering; genome-wide; immortalized cell; in vivo; inhibitor/antagonist; innovation; isocitrate; mutant; novel; novel therapeutic intervention; progenitor; public health relevance; pyruvate dehydrogenase; response; tool; tumor; tumor growth; 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（应用程序提供）：本应用的目的是测试以下假设：突变体异念力酸盐脱氢酶（IDH）的新形态活性不仅在产生oncometabolite 2-羟基卢塔特（Hydroxygluatarte）（2-HG）的产生中，而且在代谢重新编程中对tumor的进度和tumoR的范围进行了良好的治疗，因此可以对tumoR进行分析。第二个目标是识别新型成像生物标志物，以监测通过治疗的代谢重编程的归一化。 IDH是催化异位酸的氧化脱羧为�-酮戊二酸（® -kg）的酶。突变体IDH催化-kg的转化为2 -Hg。 IDH和2-HG的突变发生在超过70％的神经胶质瘤和继发性胶质母细胞瘤（GBM）中，而IDH突变是与低级脑肿瘤的开始有关的早期事件。在UCSF进行的患者活检的1H磁共振光谱（MRS）研究证实，2-Hg水平与突变体IDH表达相关。另外，观察到稳态代谢产物水平的其他几种改变。针对表达突变体IDH的细胞的初步研究概括了在患者样品中观察到的1H MRS可检测代谢变化，而13C MRS则证实，在突变体IDH细胞中，优选地转换为2-Hg。此外，发现通过代谢途径的通量发现可以复制� -kg升高并抑制一种这样的途径，从而抑制了突变体IDH细胞中细胞增殖的抑制。这些发现构成了我们假设的基础，即突变体IDH导致代谢重编程对于突变体IDH肿瘤生长至关重要。我们建议通过以下目的在基于GBM的模型以及新颖的永生星形胶质细胞和神经胶质祖细胞模型中检验这一假设。目标1。通过野生型和突变体IDH细胞中的特定代谢途径测量通量，以确定突变体IDH改变了哪些代谢途径。我们将研究野生型和突变的IDH细胞，并使用13C标记的代谢前体（超极化和热极化）以及1H MRS和完整的生物学方法的13C MRS来探测由突变体IDH调节代谢物的稳态水平的代谢途径。目标2。确定与突变体IDH相关的代谢变化是否对于细胞转化和增殖至关重要。我们将调节在突变体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thomorigenicity的后果。目的3。在体内研究突变的IDH原位脑肿瘤，以确定代谢调节的作用，并确定基于MR的生物标志物对代谢调节的反应。我们将使用MRI，1H和13C MRS/I以及完整的生物学测定方法来研究抑制代谢对突变体IDH肿瘤生长和MRS可检测生物标志物的影响。