Defining the role of mutant IDH in glioma initiation and maintenance

定义突变 IDH 在神经胶质瘤发生和维持中的作用

基本信息

批准号：
8461184
负责人：
Sheri L Holmen
金额：
$ 31.47万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461184
关键词：
Active Sites Adult Affect Amino Acids Anaplastic astrocytoma Apoptosis Arginine Astrocytes Astrocytoma Autophagocytosis Binding Biological Models Biology Brain Brain Neoplasms Cells Central Nervous System Neoplasms Decarboxylation Development Differentiation and Growth Diffuse Disease Doxycycline Enzymes Epidermal Growth Factor Receptor Etiology Event Gene Targeting Genes Genetic Suppression Glioblastoma Glioma Growth Hypoxia Inducible Factor In Vitro Isocitrate Dehydrogenase Isocitrates Lesion Link Maintenance Malignant - descriptor Malignant Neoplasms Metabolism Missense Mutation Modeling Molecular Morbidity - disease rate Mutate Mutation NADP Names Oncogenic Outcome Pathogenesis Pathway interactions Patients Phenotype Play Primary Brain Neoplasms Process Proteins Radiation Reactive Oxygen Species Reduced Glutathione Risk Role Sampling Somatic Cell System TP53 gene Testing Tetracyclines Tumor Suppressor Genes Tumor Suppressor Proteins Vascular Endothelial Growth Factors World Health Organization angiogenesis cell growth cell motility cell type cofactor combat conventional therapy cytotoxic gain of function gene delivery system hypoxia inducible factor 1 improved in vivo isocitrate loss of function mouse model mutant neoplastic cell novel outcome forecast oxidative DNA damage response temozolomide tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Gliomas are the most common primary central nervous system tumor but the molecular mechanisms responsible for the development and progression of these tumors are far from being completely understood. Recently, high-throughput sequencing of grade IV glioblastoma multiforme (GBM) tumors identified a novel mutation in isocitrate dehydrogenase 1 (IDH1) in 12% of the samples analyzed. Further studies have found this mutation to be present in ~80% of grade II-III gliomas and secondary GBM. This mutation has never before been linked to cancer and the function remains unclear. This residue is located in the active site of the enzyme and is critical for isocitrate binding. IDH proteins generate reduced NADPH from NADP+ by catalyzing the oxidative decarboxylation of isocitrate to 1-ketoglutarate (1-KG). The mutant protein has been suggested to function as a tumor suppressor due to its impaired enzymatic activity. Prolylhydroxylases, which hydroxylate and induce the degradation of hypoxia-inducible factor 11 (HIF-11), require 1-KG; therefore, decreased IDH activity may stabilize HIF-11. Activation of this pathway leads to the induction of HIF-1 target genes that affect angiogenesis, metabolism, growth and differentiation, apoptosis and autophagy, as well as cell motility. However, IDH mutations are heterozygous suggesting that these mutations may be gain of function with oncogenic potential rather than loss-of-function. In vitro studies have shown that the mutated IDH1 protein takes on a new function: converting 1-KG to R(-)-2-hydroxyglutarate (2-HG) and consuming NADPH. This is supported by findings that 2-HG levels are elevated in gliomas containing an IDH1 mutation. Furthermore, accumulation of 2-HG in the brain is associated with an increased risk of developing brain tumors. The net result of either process is reduced 1-KG and NADPH, which is an important cofactor necessary to maintain normal levels of reduced glutathione to combat reactive oxygen species (ROS). Under these conditions, cells may continually accumulate ROS-induced oxidative DNA damage and increasing numbers of mutations, which can drive malignant transformation. Interestingly, the presence of an IDH mutation is an independent marker for positive prognosis. The objective of this study is to define the role of IDH mutations in glioma formation, maintenance, and response to therapy. We hypothesize that mutations in IDH contribute to glioma formation, are required for tumor maintenance, and sensitize the tumor cells to conventional therapies. To test this hypothesis we will use a well established glioma model system to determine if expression of mutant IDH confers a growth advantage to astrocytes in vitro, plays a role in the development and maintenance of gliomas in vivo, and influences response to therapy. A better understanding of the role(s) of mutant IDH in the biology of these gliomas will guide the development of new therapies to improve survival and reduce morbidity in these patients.

描述（由申请人提供）：神经胶质瘤是最常见的原发性中枢神经系统肿瘤，但导致这些肿瘤发生和进展的分子机制还远未完全了解。最近，对 IV 级多形性胶质母细胞瘤 (GBM) 肿瘤的高通量测序在 12% 的分析样本中发现了异柠檬酸脱氢酶 1 (IDH1) 的新突变。进一步的研究发现这种突变存在于约 80% 的 II-III 级神经胶质瘤和继发性 GBM 中。这种突变以前从未与癌症相关，其功能仍不清楚。该残基位于酶的活性位点，对于异柠檬酸结合至关重要。 IDH 蛋白通过催化异柠檬酸氧化脱羧为 1-酮戊二酸 (1-KG)，从 NADP+ 生成还原的 NADPH。由于其酶活性受损，突变蛋白被认为可以充当肿瘤抑制因子。脯氨酰羟化酶可羟基化并诱导缺氧诱导因子 11 (HIF-11) 降解，需要 1-KG；因此，降低 IDH 活性可能会稳定 HIF-11。该通路的激活会诱导 HIF-1 靶基因的产生，从而影响血管生成、代谢、生长和分化、细胞凋亡和自噬以及细胞运动。然而，IDH 突变是杂合的，表明这些突变可能是具有致癌潜力的功能获得，而不是功能丧失。体外研究表明，突变的 IDH1 蛋白具有新功能：将 1-KG 转化为 R(-)-2-羟基戊二酸 (2-HG) 并消耗 NADPH。含有 IDH1 突变的神经胶质瘤中 2-HG 水平升高的研究结果支持了这一点。此外，大脑中 2-HG 的积累与患脑肿瘤的风险增加有关。任一过程的最终结果都是减少 1-KG 和 NADPH，这是维持还原型谷胱甘肽正常水平以对抗活性氧 (ROS) 所必需的重要辅助因子。在这些条件下，细胞可能会不断积累 ROS 诱导的氧化 DNA 损伤和越来越多的突变，从而导致恶性转化。有趣的是，IDH 突变的存在是积极预后的独立标志。本研究的目的是确定 IDH 突变在神经胶质瘤形成、维持和治疗反应中的作用。我们假设 IDH 突变有助于神经胶质瘤的形成，是肿瘤维持所必需的，并使肿瘤细胞对常规疗法敏感。为了检验这一假设，我们将使用一个完善的神经胶质瘤模型系统来确定突变 IDH 的表达是否赋予星形胶质细胞体外生长优势，在体内神经胶质瘤的发育和维持中发挥作用，并影响对治疗的反应。更好地了解突变 IDH 在这些神经胶质瘤生物学中的作用将指导新疗法的开发，以提高这些患者的生存率并降低发病率。