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: 10628043
• 负责人: Sriram Venneti
• 金额: $ 30.02万
• 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/10628043
• 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; Proliferating; Resistance; Therapeutic; Translating; 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