Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)

项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)

• 批准号: 10245086
• 负责人: WILLIAM G. KAELIN
• 金额: $ 34.13万
• 依托单位: BRIGHAM AND WOMEN'S 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245086
• 关键词: 3-Dimensional; Address; Aftercare; Age; Anabolism; Autophagocytosis; Basic Science; Biological Markers; Biological Models; Blood - brain barrier anatomy; Brain Glioblastoma; Brain Neoplasms; Cancer Therapy Evaluation Program; Cell Survival; Cells; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Clinical Trials; Collection; Complement; Consumption; Critical Pathways; DHODH gene; DNA; DNA Repair; Data; Dependence; Development; Dihydroorotate dehydrogenase; Dioxygenases; Drug Targeting; Enrollment; Ensure; Enzymes; Epigenetic Process; Excision; Family; Funding; Genes; Genetic; Genomics; Glioblastoma; Glioma; Glutamates; Glutaminase; Goals; Hypersensitivity; Hypoxia; Image; Imaging Techniques; Imaging technology; Isocitrate Dehydrogenase; Lead; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methodology; Mission; Mixed Function Oxygenases; Modeling; Molecular; Monitor; Mutation; Oncogenes; Oncogenic; Oncoproteins; Operative Surgical Procedures; Outcome; Pathogenesis; Patient Monitoring; Patients; Pharmacodynamics; Pharmacology; Poly(ADP-ribose) Polymerases; Polymerase; Pre-Clinical Model; Procollagen-Proline Dioxygenase; Production; Protocols documentation; Public Health; Pyrimidine; Pyrimidine Nucleotides; Radiation therapy; Radiosensitization; Recurrence; Ribose; Role; Safety; Scanning; Screening Result; Signal Transduction; Structure; Techniques; Testing; Therapeutic; Tumor Burden; United States National Institutes of Health; Variant; Work; alpha ketoglutarate; base; brain tissue; cancer cell; cytotoxicity; design; detection method; enzyme pathway; epigenome; histone demethylase; homologous recombination; imaging biomarker; improved; in vivo; inhibitor/antagonist; insight; leukemia; magnetic resonance spectroscopic imaging; member; mutant; mutational status; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; patient response; pre-clinical; programs; response; satisfaction; screening; small molecule; small molecule libraries; spectroscopic imaging; targeted treatment; therapeutically effective; treatment response; tumor; tumor growth

Discovery of a recurrent hotspot IDH1 mutation in the vast majority of low-grade gliomas and secondary glioblastomas has revolutionized our understanding of the molecular pathogenesis of these malignancies. The canonical glioma-associated IDH1 mutation encodes a mutant isocitrate dehydrogenase enzyme, IDH1 R132H, that gains the neomorphic ability to convert 2-oxoglutarate (2-OG) to the ‘oncometabolite’ R-2-hydroxyglutarate (2-HG). Consequently, 2-HG accumulates to millimolar levels in IDH1 mutant gliomas, representing a 100- to 1000-fold increase relative to normal brain tissue. The structural similarity between 2-HG and 2-OG enables 2-HG to competitively modulate the activity of many 2-OGdependent dioxygenases, including JmjC family histone demethylases, TET family DNA hydroxylases, and the hypoxia-responsive prolyl hydroxylase EglN1. Studies from our group and others demonstrate fundamental roles for epigenetic rewiring and HIF1alpha suppression in the oncogenic program induced by IDH1 mutations in glioma. Although our understanding of the function of the IDH1 R132H oncoprotein has expanded tremendously, successful exploitation of the inherent difference in 2-HG content between normal and malignant brain tissue to improve clinical outcomes has not yet been realized. Our proposal seeks to address this impediment to progress in two ways. First, we aim to use 2-HG as a biomarker of IDH mutational status and optimize methodology to quantify this metabolite non-invasively through magnetic resonance spectroscopy (MRS) imaging. We hypothesize that MRS-generated 3D maps of 2HG concentration could be used as a complement to traditional T2/FLAIR imaging to enable more precise delineation of tumor boundaries and yield improvements in the efficiency of surgical resection and the quantification of therapeutic responses in glioma patients. Furthermore, 2HG 3D MRS imaging represents an ideal approach to assess pharmacodynamic responses in patients enrolled in ongoing clinical trials of IDH targeting therapeutics. Second, we aim to develop novel therapeutic strategies designed to preferentially eradicate IDH1 mutant glioma cells by targeting vulnerabilities engendered by high 2-HG accumulation. Pharmacological inhibitors of mutant IDH enzymes have shown remarkable activity in IDH mutant leukemia but early clinical data suggest that such inhibitors will be considerably less active in IDH mutant gliomas. An alternative approach to directly targeting mutant IDH enzymes entails the exploitation of synthetic lethality with the IDH1- R132H oncogene. We have undertaken orthogonal hypothesis-driven and screening-based approaches to identify NAD+ metabolism and de novo pyrimidine synthesis as targetable vulnerabilities in IDH1 mutant glioma cells. We propose to evaluate the safety and efficacy of targeting these metabolic pathways in preclinical models of IDH1 mutant glioma to establish rationale for clinical studies of these novel therapeutic strategies.

在绝大多数低级别胶质瘤中发现复发性热点 IDH1 突变 继发性胶质母细胞瘤彻底改变了我们对这些疾病分子发病机制的理解 恶性肿瘤。典型的神经胶质瘤相关 IDH1 突变编码突变异柠檬酸脱氢酶 酶 IDH1 R132H，具有将 2-酮戊二酸 (2-OG) 转化为 “致癌代谢物”R-2-羟基戊二酸 (2-HG)。因此，2-HG 在 IDH1 中累积至毫摩尔水平 突变神经胶质瘤，相对于正常脑组织增加了 100 至 1000 倍。结构性 2-HG 和 2-OG 之间的相似性使 2-HG 能够竞争性调节许多 2-OG 依赖性的活性 双加氧酶，包括 JmjC 家族组蛋白去甲基酶、TET 家族 DNA 羟化酶以及 缺氧反应性脯氨酰羟化酶 EglN1。我们小组和其他人的研究表明了基本原理 表观遗传重连和 HIF1α 抑制在 IDH1 突变诱导的致癌程序中的作用 在神经胶质瘤中。尽管我们对 IDH1 R132H 癌蛋白的功能的了解已经扩大 巨大地，成功地利用了正常和正常之间 2-HG 含量的固有差异 改善恶性脑组织的临床结果尚未实现。我们的建议旨在解决 这在两个方面阻碍了进展。 首先，我们的目标是使用 2-HG 作为 IDH 突变状态的生物标志物，并优化方法 通过磁共振波谱 (MRS) 成像非侵入性地量化这种代谢物。我们 假设 MRS 生成的 2HG 浓度 3D 地图可以用作传统方法的补充 T2/FLAIR 成像能够更精确地描绘肿瘤边界并提高肿瘤产量 神经胶质瘤患者手术切除的效率和治疗反应的量化。此外， 2HG 3D MRS 成像是评估患者药效反应的理想方法 参加了正在进行的 IDH 靶向治疗的临床试验。 其次，我们的目标是开发新的治疗策略，旨在优先根除 IDH1 通过针对高 2-HG 积累产生的脆弱性来治疗突变神经胶质瘤细胞。药理作用 突变 IDH 酶抑制剂在 IDH 突变白血病中表现出显着的活性，但早期临床 数据表明，此类抑制剂在 IDH 突变神经胶质瘤中的活性要低得多。另一种选择 直接靶向突变 IDH 酶的方法需要利用 IDH1- 的合成致死作用 R132H 癌基因。我们采用了正交假设驱动和基于筛选的方法来 确定 NAD+ 代谢和从头嘧啶合成是 IDH1 突变神经胶质瘤的可靶向脆弱性 细胞。我们建议在临床前评估针对这些代谢途径的安全性和有效性 IDH1 突变神经胶质瘤模型，为这些新型治疗策略的临床研究奠定基础。