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

• 批准号: 8330401
• 负责人: Sheri L Holmen
• 金额: $ 38.68万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330401
• 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

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（申请人提供）：胶质瘤是最常见的原发性中枢神经系统肿瘤，但这些肿瘤发生发展的分子机制尚不完全清楚。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级胶质瘤和继发性GBM中。这种突变以前从未与癌症联系起来，其功能也尚不清楚。这种残基位于酶的活性位点，对异柠檬酸盐的结合至关重要。IDH蛋白通过催化异柠檬酸盐氧化脱羧生成1-酮戊二酸盐（1-KG），从NADP+生成还原性NADPH。由于其酶活性受损，该突变蛋白被认为具有肿瘤抑制作用。羟化并诱导缺氧诱导因子11 （HIF-11）降解的脯氨酸羟化酶需要1 kg；因此，降低IDH活性可以稳定HIF-11。该通路的激活导致HIF-1靶基因的诱导，影响血管生成、代谢、生长和分化、凋亡和自噬以及细胞运动。然而，IDH突变是杂合的，这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蛋白具有新的功能：将1-KG转化为R(-)-2-羟戊二酸（2-HG）并消耗NADPH。2-HG水平在含有IDH1突变的胶质瘤中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。任何一个过程的净结果是减少1公斤和NADPH，这是维持正常水平的还原型谷胱甘肽对抗活性氧（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DNA氧化损伤和越来越多的突变，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志。本研究的目的是确定IDH突变在胶质瘤形成、维持和治疗反应中的作用。我们假设IDH的突变有助于胶质瘤的形成，是肿瘤维持所必需的，并使肿瘤细胞对常规治疗敏感。为了验证这一假设，我们将使用一个完善的胶质瘤模型系统来确定突变型IDH的表达是否在体外赋予星形胶质细胞生长优势，是否在体内胶质瘤的发展和维持中发挥作用，以及是否影响对治疗的反应。更好地了解突变IDH在这些胶质瘤生物学中的作用将指导新疗法的发展，以提高这些患者的生存率和降低发病率。