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: 10708134
• 负责人: Andrea Piunti
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708134
• 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; Bromodomains and extra-terminal domain inhibitor; CRISPR screen; Cell Proliferation; Cell Separation; Cells; Characteristics; Chemosensitization; Child; Childhood; Childhood Brain Stem Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Solid Neoplasm; Chromatin; Clinical; Combined Modality Therapy; Complex; Data; Deposition; Diagnosis; Diffuse; Diffuse intrinsic pontine glioma; Disease; Disease Progression; Epigenetic Process; Event; Exclusion; Gene Expression; Gene Expression Profile; Gene Silencing; Generations; Genes; Genetic; Genetic Engineering; Genetic Transcription; Glioma; Goals; H3 K27M mutation; Heterozygote; Histone H3; Histones; In Vitro; Incidence; Knowledge; Lysine; Maintenance; Measures; Mediating; Mentors; Methionine; Methylation; Modeling; Molecular; Molecular Biology; Mus; Mutation; Nucleosomes; Oncogenic; Outcome; Pathogenicity; Pathway interactions; Patients; 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; efficacious treatment; epigenome; experimental study; genome-wide; improved; in vivo; inhibitor therapy; insight; mortality; mouse model; mutant; neoplastic cell; pharmacologic; 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

扩散 特征化的 组蛋白 替代 级别 通过分析表观基因组 H3K27M 突变 DIPG 患者细胞 我发现 H3K27M 与 H3K27 共定位 乙酰化（H3K27ac）。根据之前的生化数据，异型H3K27M- K27ac 核小体与溴结构域蛋白共定位于活跃转录的基因处， 而 PRC2 被排除在这些区域之外，这表明 PRC2 并未被隔离在 H3K27M 的合并。我还表明异型核小体 H3K27M-K27ac 共同 用 DIPG 中的溴结构域蛋白进行定位，重要的是用 BET 溴结构域进行处理 DIPG 异种移植小鼠模型中的抑制剂可有效减少肿瘤生长并延长动物寿命 生存。在我的指导阶段（K99），我计划研究分子细节 利用体外生物化学和分子生物学形成异型核小体 分析并收集有关异常乙酰化和的致病机制的进一步见解 H3K27M 在 DIPG 中沉积。在向独立阶段（R00）过渡时，我 计划通过确定 BET 抑制剂的机制来改进治疗策略 抵抗和合作因素可以为儿童带来改进和持久的治疗 受 DIPG 影响。总而言之，我的计划是进行实验来推动我们的 对这种不治之症的了解，目的是最终拥有一种标准护理选择 可为DIPG患者提供可靠、有效的治疗。 内在神经胶质瘤（DIP G）是一种高度侵袭性的儿童脑干肿瘤 患者迅速且几乎一致的死亡。杂合点突变 H3 出现在超过 80% 的此类肿瘤中，并导致赖氨酸转化为蛋氨酸 （H3K27M）。该组蛋白突变体的表达伴随着 Polycomb 抑制复合物 2 (PRC2) 介导的 H3K27 三甲基化 (H3K27me3) 这被假设为 DIPG 肿瘤发生的驱动事件。 桥桥是