Unraveling metabolic dependencies in H3K27M mutant Diffuse Intrinsic Pontine Gliomas

项目总结/摘要 尽管我们对弥漫性内在脑桥胶质瘤的分子驱动因素的理解有了重大进展， （DIPG），没有可行的治疗选择，导致DIPG患者的某些死亡。缺乏 对DIPG发病机理的理解是治愈这些侵袭性肿瘤的重要障碍。超过80% 的DIPG在赖氨酸27处携带组蛋白H3突变为甲硫氨酸（H3 K27 M），这导致DIPG的总体减少。 压制性标记H3 K27 me 3有证据表明H3 K27 M是肿瘤发生的中心驱动因素，但H3 K27 M在肿瘤发生过程中起着重要作用。 精确的机制仍然不清楚。阐明H3 K27 M突变的分子机制 驱动癌症和调节H3 K27 me 3的精确机制可以阐明潜在的治疗方法， 接近。驱动癌细胞存活和生长的基本机制之一是癌细胞的重编程。 癌基因的细胞代谢，这使得增加营养素的吸收和代谢， 葡萄糖和谷氨酰胺。谷氨酰胺是最丰富的血浆氨基酸，其支持 不受控制的癌细胞生长和增殖。谷氨酰胺代谢为α-酮戊二酸（αKG）， 作为三羧酸（TCA）循环的底物，因此对ATP合成、氧化还原 体内平衡和生物分子的产生。更重要的是，谷氨酰胺衍生的αKG是 H3 K27组蛋白赖氨酸脱甲基酶（KDM），其可以驱动H3 K27 me 3的整体还原。谷氨酰胺是 因此，在几个交叉途径的十字路口，既是支持癌症的关键代谢物， 生长和驱动H3 K27 me 3减少的辅因子，这是H3 K27 M突变DIPG发病机制的核心。 我们的总体假设是H3 K27 M DIPG细胞通过以下途径重新连接细胞代谢和表观遗传学： 谷氨酰胺以维持不受控制的肿瘤生长和增殖。三个具体目标将解决这一问题 假设：目标1。定义谷氨酰胺代谢并阐明H3 K27 M 增强谷氨酰胺代谢。目标2.探究谷氨酰胺 代谢调节整体H3 K27 me 3减少。目标3：阐明靶向治疗的潜力 谷氨酰胺代谢作为原理证明。将这三个目标结合起来， 我们对DIPG的理解，并为开发有效的治疗方法奠定基础。

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.