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经有了很大的 临床影响。最近，大规模的测序研究已经确定了复发的、功能获得的idh基因。 胶质母细胞瘤的一个重要亚群的突变，在年轻的恶性胶质瘤中特别丰富 成年人(18-45岁)。该突变酶催化合成新的肿瘤代谢物2- 羟基戊二酸(2-HG)。2-羟色胺水平升高抑制依赖2-羟基戊二酸的双加氧酶 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学 控制基因表达，这被认为是促进肿瘤发生的因素。因为未在以下位置找到2-HG 在正常细胞中，基础水平通过2-HG脱氢酶被清除， 在人脑胶质瘤中积累到毫摩尔水平，表明它可能是突变的理想生物标志物。 酶活性。了解现有肿瘤对突变IDHI活性的要求，以及2- HG水平可作为患者突变酶活性的替代指标 开发这种疾病的新的靶向治疗方法。在初步研究中，我们和其他人有 描述了诱导治疗反应的生物相关性和潜在的可操作途径 在IDH突变型胶质瘤中。在项目3中，我们将使用临床材料来检验非侵入性假说 2-HG水平的测定可作为IDH突变酶活性的替代指标，并可针对 IDH突变和2-HG可能成为恶性胶质瘤治疗的新策略。 这个项目的基础科学家(W·凯林)是霍华德·休斯的研究员和分子 生物学家，临床调查员(DP卡希尔)是一名执业神经外科医生。高岭土博士的团队帮助 确定IDHI突变和2-HG产生对猪的表观基因组的功能代谢影响 第一个证明突变的IDH1可以在体外转化人类星形胶质细胞，也是第一个 证明一种潜在的治疗干预措施(EglN抑制)可以选择性地针对异常 1DH1突变肿瘤内的生化环境。卡希尔博士的实验室进行了IDH层析 最近的国家胶质母细胞瘤RTOG-0525试验，以及他的同事，已经建立了IDHI突变 从新鲜切除的患者肿瘤标本衍生的原位异种移植胶质瘤模型。我们相信 项目3的成功实施将支持1DH1突变体临床试验的未来发展 神经胶质瘤。