Targeting the IDH Pathway

靶向 IDH 通路

• 批准号: 8588493
• 负责人: WILLIAM G. KAELIN
• 金额: $ 32.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588493
• 关键词: Age; Age-Years; Astrocytes; Biochemical; Biological; Biological Markers; Cancer Etiology; Cause of Death; Cell physiology; Cells; Cessation of life; Chromatin Structure; Clinical; Clinical Investigator; Clinical Trials; Detection; Development; Dioxygenases; Disease; Environment; Enzymes; Epigenetic Process; Event; Future; Gene Expression; Gene Mutation; Genetic; Genomics; Glioblastoma; Glioma; Human; In Vitro; Isocitrate Dehydrogenase; Kaolin; Large-Scale Sequencing; Magnetic Resonance Spectroscopy; Malignant Glioma; Measurement; Measures; Metabolic; Methods; Modeling; Molecular; Mus; Mutation; Neurosurgeon; Normal Cell; Oncogenic; Oxidoreductase; Pathway interactions; Patients; Production; Radiation Therapy Oncology Group; Recurrence; Research Personnel; Resected; Sampling; Scientist; Stratification; Testing; Therapeutic; Therapeutic Intervention; Woman; Work; Xenograft Model; Xenograft procedure; alpha ketoglutarate; cancer cell; clinical material; design; enzyme activity; epigenome; gain of function; in vivo; men; middle age; mutant; novel; novel therapeutics; response; therapeutic target; tool; tumor; tumorigenesis; young adult

Targeted therapeutics designed against specific oncogenic genomic alterations have had a large clinical impact. Recently, large-scale sequencing studies have identified recurrent, gain-of-function IDH gene mutations in a significant subset of glioblastomas, with particular enrichment in malignant gliomas of younger adults (age 18-45). The mutant enzyme catalyzes the production of the novel oncometabolite 2- hydroxyglutarate (2-HG). Increased levels of 2-HG inhibits the 2-oxoglutarate dependent dioxygenase class of enzymes in cells that impact a range of cellular functions including chromatin structure and the epigenetic control of gene expression, which are thought to promote tumorigenesis. Because 2-HG is not found at appreciable quantities in normal cells, where basal levels are cleared via 2-HG dehydrogenase, the accumulation to millimolar levels in human gliomas suggests that it could be an ideal biomarker for mutant enzyme activity. Understanding the requirements for mutant IDHI activity in existing tumors, and whether 2- HG levels can serve as a surrogate for mutant enzyme activity in patients are critical issues for the development of new targeted therapies in this disease. In preliminary studies, we and others have characterized the biological correlates and potentially actionable avenues for inducing therapeutic response in IDH mutant gliomas. In Project 3, we will use clinical material to test the hypotheses that non-invasive measurement of 2-HG levels can serve as surrogate for IDH mutant enzyme activity, and that targeting of IDH mutation and 2-HG may be a novel therapeutic strategy for malignant glioma patients. The basic scientist on this project (W Kaelin) is a Howard Hughes Investigator and molecular biologist, and the clinical investigator (DP Cahill) is a practicing neurosurgeon. Dr Kaolin's group helped define the functional metabolic consequences of IDHI mutation and 2-HG production on the epigenome of cancer cells, was the first to show that mutant IDH1 transforms human astrocytes in vitro, and was the first to demonstrate that a potential therapeutic intervention (EglN inhibition) can selectively target the abnormal biochemical environment within 1DH1 mutant tumors. Dr. Cahill's lab performed IDH stratification ofthe recent national RTOG-0525 trial in glioblastoma, and with his colleagues, has established IDHI-mutant orthotopic xenograft glioma models derived from freshly resected patient tumor samples. We believe that the successful execution of Project 3 will support the future development of clinical trials for 1DH1 mutant gliomas.

针对特定致癌基因组改变而设计的靶向治疗已取得了巨大的成功 临床影响。最近，大规模测序研究发现了复发性、功能获得性 IDH 基因 胶质母细胞瘤的一个重要亚型中存在突变，特别是年轻的恶性胶质瘤中的突变 成人（18-45 岁）。突变酶催化新型肿瘤代谢物 2- 的产生 羟基戊二酸（2-HG）。 2-HG 水平升高会抑制 2-酮戊二酸依赖性双加氧酶类 细胞中影响一系列细胞功能的酶，包括染色质结构和表观遗传 基因表达的控制，被认为促进肿瘤发生。因为 2-HG 未发现于 正常细胞中的量相当可观，其中基础水平通过 2-HG 脱氢酶清除， 在人类神经胶质瘤中积累至毫摩尔水平表明它可能是突变体的理想生物标志物 酶活性。了解现有肿瘤中突变 IDHI 活性的要求，以及是否 2- HG 水平可以作为患者突变酶活性的替代物，这是对于 开发针对该疾病的新靶向疗法。在初步研究中，我们和其他人已经 描述了诱导治疗反应的生物学相关性和潜在可行的途径 IDH 突变神经胶质瘤。在项目3中，我们将使用临床材料来检验非侵入性治疗的假设 2-HG 水平的测量可以作为 IDH 突变酶活性的替代物，并且靶向 IDH突变和2-HG可能是恶性胶质瘤患者的一种新的治疗策略。 该项目的基础科学家（W Kaelin）是霍华德休斯研究员和分子生物学家 生物学家，临床研究者（DP Cahill）是一名执业神经外科医生。 Kaolin 博士的团队提供了帮助 定义 IDHI 突变和 2-HG 产生对表观基因组的功能代谢影响 癌细胞，第一个在体外证明突变型 IDH1 可以转化人类星形胶质细胞，并且是第一个 证明潜在的治疗干预（EglN 抑制）可以选择性地针对异常 1DH1突变肿瘤内的生化环境。 Cahill 博士的实验室对 最近，他与同事一起进行了针对胶质母细胞瘤的国家 RTOG-0525 试验，确定了 IDHI 突变体 来自新鲜切除的患者肿瘤样本的原位异种移植神经胶质瘤模型。我们相信 项目3的成功执行将支持未来1DH1突变体临床试验的开展 神经胶质瘤。