Unraveling metabolic dependencies in H3K27M mutant Diffuse Intrinsic Pontine Gliomas

揭示 H3K27M 突变体弥漫性内源性脑桥胶质瘤的代谢依赖性

• 批准号: 10175067
• 负责人: Sriram Venneti
• 金额: $ 30.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175067
• 关键词: ATP Synthesis Pathway; Address; Amino Acids; Animal Model; Automobile Driving; Biology; Brain; Brain Stem; Cell Proliferation; Cell Survival; Cells; ChIP-seq; Child; Childhood Brain Neoplasm; Chromatin; Citric Acid Cycle; Clinical Trials; DNA Modification Process; Data; Dependence; Development; Diffuse intrinsic pontine glioma; Disease Progression; Effectiveness; Enzymes; Epigenetic Process; FDA approved; Gene Expression; Generations; Genetic; Genomics; Glucose; Glutamate Dehydrogenase; Glutaminase; Glutamine; Growth; H3 K27M mutation; Heart; Histone H3; Histones; Homeostasis; Human; Implant; In Vitro; Isotope Labeling; Knowledge; Label; Location; Lysine; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methods; Molecular; Monitor; Mus; Mutation; Oncogenes; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Plasma; Pontine structure; Positron-Emission Tomography; Production; Resistance; Therapeutic; Translating; Ursidae Family; Withdrawal; Work; alpha ketoglutarate; cancer cell; cell growth; cofactor; effective therapy; genomic locus; histone modification; in vivo; mouse model; nerve stem cell; nutrient metabolism; patient derived xenograft model; transcriptome sequencing; tumor; tumor growth; tumorigenesis; uptake

Project Summary/ Abstract Despite significant advances in our understanding of the molecular drivers of Diffuse Intrinsic Pontine Gliomas (DIPGs), there are no viable treatment options resulting in certain fatality of DIPG patients. The lack of understanding of DIPG pathogenesis is a significant barrier to curing these aggressive tumors. More than 80% of DIPGs bear a histone H3 mutation at lysine 27 to methionine (H3K27M) which leads to global reduction of the repressive mark H3K27me3. Evidence implicates H3K27M as a central driver of tumorigenesis, yet the precise mechanisms remain obscure. Elucidation of the molecular mechanisms by which H3K27M mutations drive cancer and the precise mechanisms that regulate H3K27me3 could illuminate potential therapeutic approaches. One of the fundamental mechanisms driving cancer cell survival and growth is reprograming of cellular metabolism by oncogenes, which enables increased uptake and metabolism of nutrients such as glucose and glutamine by tumors. Glutamine is the most abundant plasma amino acid, which supports uncontrolled growth and proliferation of cancer cells. Glutamine is metabolized to α-ketoglutarate (αKG), which serves as a substrate for the tricarboxylic acid (TCA) cycle and is thereby critical for ATP synthesis, redox homeostasis and production of biomolecules. More importantly, glutamine-derived αKG is a critical cofactor for the H3K27 histone lysine demethylases (KDMs) that can drive global reduction of H3K27me3. Glutamine is therefore at the crossroads of several intersecting pathways, both a critical metabolite that supports cancer growth and a cofactor to drive H3K27me3 reduction that is central to pathogenesis of H3K27M mutant DIPGs. Our global hypothesis is that H3K27M DIPG cells rewire both cellular metabolism and epigenetics via glutamine to sustain uncontrolled tumor growth and proliferation. Three specific aims will address this hypothesis: Aim 1. Define glutamine metabolism and elucidate the epigenetic mechanisms by which H3K27M enhances glutamine metabolism. Aim 2. Interrogate the molecular mechanisms by which glutamine metabolism regulates global H3K27me3 reduction. Aim 3. Elucidate the therapeutic potential of targeting glutamine metabolism as proof-of-principle. The combination of these three aims will address significant gaps in our understanding of DIPGs and lay the groundwork to develop effective treatments.

项目摘要/摘要 尽管我们对弥漫性固有桥脑胶质瘤的分子驱动因素的理解取得了重大进展 (DIPGs)，没有可行的治疗选择，导致DIPG患者的某些死亡。缺乏 了解DIPG的发病机制是治疗这些侵袭性肿瘤的重要障碍。80%以上 的DIPG在27位赖氨酸携带组蛋白H3突变为蛋氨酸(H3K27M)，导致全球范围内 压抑的标记H3K27me3。有证据表明H3K27M是肿瘤发生的核心驱动因素，但 确切的机制仍然不清楚。H3K27M突变的分子机制研究 致癌和调控H3K27me3的精确机制可能阐明潜在的治疗方法 接近了。驱动癌细胞存活和生长的基本机制之一是重新编程 癌基因的细胞代谢，这使得营养物质的吸收和代谢增加，如 由肿瘤引起的葡萄糖和谷氨酰胺。谷氨酰胺是血浆中含量最丰富的氨基酸，它支持 癌细胞的不受控制的生长和增殖。谷氨酰胺被代谢成α-酮戊二酸(αKG)，后者 作为三羧酸(TCA)循环的底物，因此对ATP合成、氧化还原至关重要 动态平衡与生物分子的产生。更重要的是，谷氨酰胺衍生的αKG是 H3K27组蛋白赖氨酸去甲基酶(KDM)，可推动H3K27me3的全球还原。谷氨酰胺是 因此，在几条交叉途径的十字路口，两者都是支持癌症的关键代谢物 生长和驱动H3K27me3还原的辅因子，这是H3K27M突变DIPGs发病的核心。 我们的全球假设是，H3K27M DIPG细胞通过 谷氨酰胺以维持不受控制的肿瘤生长和增殖。解决这一问题的具体目标有三个 假设：目的1.定义谷氨酰胺代谢并阐明H3K27M的表观遗传学机制 增强谷氨酰胺新陈代谢。目的2.探讨谷氨酰胺的分子机制 代谢调节全球H3K27me3的还原。目的3.阐明靶向治疗的潜力 谷氨酰胺代谢作为原则证据。这三个目标的结合将解决重大差距。 在我们对DIPGs的理解中，为开发有效的治疗方法奠定了基础。