Targeting the IDH Pathway

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进展。 临床影响。最近，大规模的测序研究已经确定了复发性，功能获得性IDH基因 在胶质母细胞瘤的重要亚群中存在突变，特别是在年轻人的恶性胶质瘤中富集。 成人（18-45岁）。该突变酶催化新的癌代谢物2- 羟戊二酸（2-HG）。2-HG水平升高抑制2-酮戊二酸依赖性双加氧酶类 影响细胞功能的酶，包括染色质结构和表观遗传 控制基因表达，这被认为是促进肿瘤发生。因为2-HG不存在于 在正常细胞中，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中突变IDHI活性的要求，以及2- HG水平可以作为患者中突变酶活性的替代物，这是本发明的关键问题。 在这种疾病中开发新的靶向疗法。在初步研究中，我们和其他人 表征了生物学相关性和诱导治疗反应的潜在可行途径 IDH突变型神经胶质瘤在项目3中，我们将使用临床材料来检验非侵入性 2-HG水平的测量可以作为IDH突变体酶活性的替代物， IDH突变和2-HG可能成为恶性胶质瘤治疗的新策略。 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，临床研究者（DP Cahill）是一名执业神经外科医生。考林博士的团队帮助 定义IDHI突变和2-HG产生对表观基因组的功能代谢后果， 癌细胞，是第一个显示突变IDH 1在体外转化人类星形胶质细胞，也是第一个 表明潜在的治疗干预（EglN抑制）可以选择性地靶向异常 1DH 1突变肿瘤内的生化环境。Cahill博士的实验室进行了IDH分层 最近在胶质母细胞瘤中进行的国家RTOG-0525试验，及其同事已经确定了IDHI突变体 来源于新鲜切除的患者肿瘤样品的原位异种移植神经胶质瘤模型。我们认为 项目3的成功实施将支持1DH 1突变体的临床试验的未来发展。 神经胶质瘤

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.