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：
8161075
负责人：
Sheri L Holmen
金额：
$ 1.02万
依托单位：
NEVADA CANCER INSTITUTE
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 2011-10-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8161075
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，但是负责这些肿瘤发展和进展的分子机制远非完全理解。最近，IV级胶质母细胞瘤（GBM）肿瘤的高通量测序鉴定了在分析的12％样品中的异氯酸酯脱氢酶1（IDH1）中的新型突变。进一步的研究发现，在约80％的II-III级神经胶质瘤和次级GBM中存在这种突变。该突变从未与癌症有关，该功能尚不清楚。该残基位于酶的活性位点，对于异位酸盐结合至关重要。 IDH蛋白通过催化异位酸的氧化脱羧为1-酮戊二酸酯（1-KG），从而产生从NADP+的NADPH降低。由于其酶促活性受损，已建议突变蛋白充当肿瘤抑制。羟基羟基酶，羟基甲酯并诱导低氧诱导因子11（HIF-11）的降解，需要1公斤；因此，IDH活性降低可能稳定HIF-11。该途径的激活导致诱导HIF-1靶基因，这些基因影响血管生成，代谢，生长和分化，凋亡和自噬以及细胞运动性。但是，IDH突变是杂合的，表明这些突变可能是具有致癌潜力而不是功能丧失的功能。体外研究表明，突变的IDH1蛋白具有新的功能：将1千克转换为R（ - ） - 2-羟基戊二酸（2-HG）和消耗NADPH。这是由含有IDH1突变的神经胶质瘤中2-HG水平升高的发现支持的。此外，大脑中2-HG的积累与患脑肿瘤的风险增加有关。这两种过程的净结果均减少1公斤和NADPH，这是维持正常水平降低的谷胱甘肽水平以对抗活性氧（ROS）的重要辅助因子。在这些条件下，细胞可能会不断积累ROS诱导的氧化性DNA损伤并增加突变，从而驱动恶性转化。有趣的是，IDH突变的存在是阳性预后的独立标记。这项研究的目的是定义IDH突变在神经胶质瘤形成，维持和对治疗反应中的作用。我们假设IDH中的突变有助于神经胶质瘤形成，维持肿瘤需要，并使肿瘤细胞对常规疗法敏感。为了检验这一假设，我们将使用建立的胶质瘤模型系统来确定突变体IDH的表达是否赋予体外星形胶质细胞的生长优势，在体内的胶质瘤的发展和维持中起作用，并影响对治疗的反应。更好地理解突变体IDH在这些神经胶质瘤生物学中的作用将指导新疗法的发展，以改善这些患者的生存和降低发病率。