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

项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)

基本信息

批准号：
10019488
负责人：
WILLIAM G. KAELIN
金额：
$ 34.64万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10019488
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 Detection 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 Treatment Efficacy Tumor Burden United States National Institutes of Health Variant Work alpha ketoglutarate base brain tissue cancer cell cytotoxicity design 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 novel therapeutics patient response pre-clinical programs response satisfaction screening small molecule small molecule libraries spectroscopic imaging targeted treatment treatment response tumor tumor growth

项目摘要

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.

在绝大多数低级神经胶质瘤中发现复发的热点IDH1突变二级胶质母细胞瘤彻底改变了我们对这些分子发病机理的理解恶性肿瘤。典型神经胶质瘤相关的IDH1突变编码突变型异位酸盐脱氢酶酶，IDH1 R132H，具有将2-氧化甲酸酯（2-OG）转换为新形态的能力 “ oncometabolite” R-2-羟基戊二酸（2-HG）。因此，2-HG在IDH1中积聚至毫米水平突变神经胶质瘤，相对于正常的脑组织，代表100至1000倍。结构 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依赖性的活性二氧酶，包括JMJC家族组蛋白脱甲基酶，TET家族DNA羟化酶和低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 IDH1突变引起的致癌程序中表观遗传重新启动和HIF1ALPHA抑制的作用在神经胶质瘤中。尽管我们对IDH1 R132H癌蛋白功能的理解已经扩展巨大的是，正常和尚未实现恶性脑组织以改善临床结果。我们的建议旨在解决这种障碍以两种方式进步。首先，我们旨在将2-HG用作IDH突变状态的生物标志物，并优化方法论通过磁共振光谱（MRS）成像量化该代谢物的非侵入剂。我们假设MRS生成的2HG浓度的3D地图可以用作传统的完成 T2/FLAIR成像以实现更精确的肿瘤边界描述，并在胶质瘤患者的手术切除效率和治疗反应的定量。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，我们旨在制定旨在优先放射性IDH1的新型治疗策略突变的神经胶质瘤细胞通过靶向高2-HG积累参与的脆弱性。药理突变IDH酶的抑制剂在IDH突变性白血病中表现出显着的活性，但早期临床数据表明，这种抑制剂在IDH突变胶质瘤中的活性较低。另一种直接靶向突变体IDH酶的方法需要用IDH1-剥削合成杀伤力 R132H癌基因。我们采取了基于正交假设驱动的和筛查的方法识别NAD+代谢和从头嘧啶合成为IDH1突变胶质瘤中的靶向漏洞细胞。我们建议评估针对临床前这些代谢途径的安全性和效率 IDH1突变胶质瘤的模型为这些新型治疗策略的临床研究建立基本原理。