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

基本信息

批准号：
10409675
负责人：
Sriram Venneti
金额：
$ 30.05万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10409675
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

项目摘要

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.

项目概要/摘要尽管我们对弥漫性内源性脑桥胶质瘤的分子驱动因素的理解取得了重大进展 (DIPG)，没有可行的治疗方案会导致 DIPG 患者死亡。了解 DIPG 发病机制是治愈这些侵袭性肿瘤 80% 以上的重大障碍。的 DIPG 在赖氨酸 27 处具有组蛋白 H3 突变为蛋氨酸 (H3K27M)，这导致整体减少抑制标记 H3K27me3 的证据表明 H3K27M 是肿瘤发生的核心驱动因素，但 H3K27M 突变的分子机制仍不清楚。驱动癌症和调节 H3K27me3 的精确机制可能会阐明潜在的治疗方法驱动癌细胞存活和生长的基本机制之一是重编程。癌基因的细胞代谢，可以增加营养物质的吸收和代谢，例如肿瘤产生的葡萄糖和谷氨酰胺谷氨酰胺是最丰富的血浆氨基酸，它支持肿瘤。癌细胞不受控制的生长和增殖被代谢为α-酮戊二酸（αKG）。作为三羧酸 (TCA) 循环的底物，因此对于 ATP 合成、氧化还原至关重要更重要的是，谷氨酰胺衍生的 αKG 是生物分子的关键辅助因子。可以驱动 H3K27me3 整体减少的 H3K27 组蛋白赖氨酸去甲基酶 (KDM) 是。因此，在几个交叉途径的十字路口，这两种途径都是支持癌症的关键代谢物生长和驱动 H3K27me3 减少的辅助因子，这是 H3K27M 突变 DIPG 发病机制的核心。我们的总体假设是 H3K27M DIPG 细胞通过重新连接细胞代谢和表观遗传学谷氨酰胺维持不受控制的肿瘤生长和增殖将解决这个问题。假设：目标 1. 定义谷氨酰胺代谢并阐明 H3K27M 的表观遗传机制目标 2. 探究谷氨酰胺的分子机制。代谢调节整体 H3K27me3 减少。目标 3. 阐明靶向治疗的潜力。谷氨酰胺代谢作为原理验证，这三个目标的结合将解决重大差距。加深我们对 DIPG 的理解，并为开发有效的治疗方法奠定基础。