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（由申请人提供）：本申请的目的是验证突变异柠檬酸脱氢酶（IDH）的新形态活性不仅导致肿瘤代谢物2-羟戊二酸（2-HG）的产生，而且还导致更广泛的代谢重编程，这是肿瘤进展所必需的，因此可以靶向治疗IDH突变胶质瘤。第二个目标是确定新的成像生物标志物，用于监测治疗过程中这种代谢重编程的正常化。IDH是催化异柠檬酸氧化脱羧成-酮戊二酸（-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起始相关的早期事件。在加州大学旧金山分校进行的患者活检的1H磁共振波谱（MRS）调查证实，2-HG水平与突变型IDH表达相关。此外，还观察到稳态代谢物水平的其他一些变化。对表达突变型IDH的细胞的初步研究再现了在患者样本中观察到的1H nmr可检测的代谢变化，13c MRS证实了在突变型IDH细胞中¿-KG优先转化为2-HG。此外，通过代谢途径补充¿-KG的通量被发现升高，其中一条途径的抑制导致突变型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，即突变型IDH导致代谢重编程，这是突变型IDH肿瘤生长所必需的。我们建议通过以下目的在基于gbm的模型以及新的永生化星形胶质细胞和胶质祖细胞模型中验证这一假设。目的1。测量野生型和突变型IDH细胞中特定代谢途径的通量，以确定突变型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和互补的生物学方法来探索控制突变型IDH代谢产物稳态水平的代谢途径。目标2。确定与突变型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，以确定代谢调节的影响，并确定对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以及补充的生物学分析来研究抑制代谢对突变型IDH肿瘤生长和MRS可检测生物标志物的影响。！