A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)

弥漫性内源性脑桥胶质瘤 (DIPG) 的分子信息疗法

• 批准号: 10015227
• 负责人: Andrea Piunti
• 金额: $ 11.44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015227
• 关键词: 6 year old; Acetylation; Acute; Address; Affect; Affinity; Amino Acids; Animals; Automobile Driving; Binding; Biochemical; Biochemistry; Biological Assay; Brain Neoplasms; Brain Stem; Bromodomain; CRISPR screen; Cell Proliferation; Cells; Characteristics; Chemosensitization; Child; Childhood; Childhood Brain Stem Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Solid Neoplasm; Chromatin; Clinical; Complex; Data; Deposition; Diagnosis; Diffuse; Diffuse intrinsic pontine glioma; Disease; Disease Progression; Epigenetic Process; Event; Gene Expression; Gene Silencing; Generations; Genes; Genetic; Genetic Engineering; Genetic Transcription; Glioma; Goals; Histone H3; Histones; In Vitro; Incidence; Knowledge; Lead; Lysine; Maintenance; Measures; Mediating; Mentors; Methionine; Modeling; Molecular; Molecular Biology; Mus; Mutation; Nucleosomes; Oncogenic; Outcome; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phase; Phase I Clinical Trials; Point Mutation; Polycomb; Pontine structure; Positioning Attribute; Property; Protein Isoforms; Proteins; Radiation therapy; Reaction; Recurrence; Regulation; Resistance; Role; Sampling; Site; System; Therapeutic; Tissues; Treatment Protocols; Universities; Work; Xenograft procedure; clinically relevant; epigenome; experimental study; genome-wide; improved; in vivo; inhibitor/antagonist; insight; mortality; mouse model; mutant; neoplastic cell; pre-clinical; recruit; resistance mechanism; small molecule inhibitor; standard of care; tumor; tumor growth; tumorigenesis

Diffuse characterized histone substitution levels and By profilying the epigenome of H3K27M mutant DIPG patient cells I found that H3K27M co-localizes with H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, heterotypic H3K27M- K27ac nucleosomes co-localize with bromodomain proteins at actively transcribed genes, whereas PRC2 is excluded from these regions, suggesting that PRC2 is not sequestered at sites of incorporation of H3K27M. I also showed that the heterotypic nucleosomes H3K27M-K27ac co- localize with bromodomain proteins in DIPG, importantly treatment with BET bromodomain inhibitors in DIPG xenograft mouse models potently reduces tumor growth and extend animal survival. During my mentored phase (K99) I'm planning to study the molecular details of the formation of the heterotypic nucleosomes using in vitro biochemistry and molecular biology assays and gather further insights in the pathogenic mechanisms of aberrant acetylation and H3K27M deposition in DIPG. While transitioning toward the independent phase (R00) I'm planning to improve the BET inhibitors therapeutic strategy by identifying mechanisms of resistance and cooperative factors that can lead to an improved and durable therapy for children affected by DIPG. Altogether my plan is to perform experiments that push forward our knowledge of this incurable disease with the goal of finally having a standard-of-care option that can offer a reliable and efficacious treatment for DIPG patients. Intrinsic Glioma (DIP G) a highly aggressive pediatric brainstem tumor by rapid and nearly uniform patient demise. A heterozygous point mutation of H3 occurs in more than 80% of these tumors, and results in a lysine-to-methionine (H3K27M). Expression of this histone mutant is accompanied by a reduction in the of Polycomb Repressive Complex 2 (PRC2) mediated H3K27 trimethylation (H3K27me3) this is hypothesized to be a driving event of DIPG oncogenesis. Pontine is

弥散特征组蛋白取代水平和通过分析表观基因组 在H3 K27 M突变型DIPG患者细胞中，我发现H3 K27 M与H3 K27共定位， 乙酰化（H3 K27 ac）。根据以前的生化数据，异型H3 K27 M- K27 ac核小体与布罗莫结构域蛋白共定位于活跃转录的基因， 而PRC 2被排除在这些区域之外，这表明PRC 2没有被隔离在 H3 K27 M的加入。我还表明，异型核小体H3 K27 M-K27 ac共- 在DIPG中用溴结构域蛋白定位，重要的是用BET溴结构域治疗 DIPG异种移植小鼠模型中的抑制剂有效地减少肿瘤生长并延长动物 生存在我的指导阶段（K99），我计划研究的分子细节， 利用体外生物化学和分子生物学形成异型核小体 分析并收集异常乙酰化的致病机制的进一步见解， DIPG中的H3 K27 M沉积。在向独立阶段（R 00）过渡的同时，我 计划通过确定以下机制来改善BET抑制剂的治疗策略： 抵抗和合作因素，可以导致改善和持久的治疗儿童 受DIPG影响。总之，我的计划是进行实验，推动我们的 对这种不治之症的了解，目的是最终有一个标准的护理选择， 可以为DIPG患者提供可靠有效的治疗。 内源性胶质瘤（DIP G）是一种高度侵袭性的小儿脑干肿瘤 迅速且几乎一致的病人死亡一个杂合子点突变， H3发生在超过80%的这些肿瘤中，并导致赖氨酸到甲硫氨酸的突变。 （H3K27M）。这种组蛋白突变体的表达伴随着蛋白质水平的降低。 多梳抑制复合物2（PRC 2）介导的H3 K27三甲基化（H3 K27 me 3） 假设这是DIPG肿瘤发生的驱动事件。 庞廷群岛