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

基本信息

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
项目类别：
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

项目摘要

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

扩散特征组蛋白替代水平并通过熟悉表观基因组 H3K27M突变体DIPG患者细胞我发现H3K27M与H3K27共定位乙酰化（H3K27AC）。根据以前的生化数据，异型H3K27M- K27AC核小体与溴结构域蛋白在主动转录的基因上共定位，尽管PRC2被排除在这些区域之外，这表明PRC2不会隔离在 H3K27M的合并。我还表明，异型核小体H3K27M-K27AC共同在DIPG中与溴结构域蛋白定位 DIPG异种移植小鼠模型中的抑制剂有效减少肿瘤的生长并延伸动物生存。在我的指导阶段（K99）中，我计划研究使用体外生物化学和分子生物学形成异型核小体测定并收集有关异常乙酰化的致病机理的进一步见解 H3K27M DIPG沉积。在向独立阶段过渡时（R00）我计划通过确定的机制来改善BET抑制剂治疗策略抗药性和合作因素，可以改善儿童的耐用疗法受DIPG的影响。我的计划完全是进行实验，以推动我们了解这种无法治愈的疾病，目的是最终拥有标准的选择可以为DIPG患者提供可靠有效的治疗方法。内在神经胶质瘤（DIP G）高度侵略性的小儿脑干肿瘤通过快速而几乎统一的患者灭亡。杂合点突变 H3发生在这些肿瘤中的80％以上，并导致赖氨酸到甲硫代（H3K27M）。该组蛋白突变体的表达伴随着降低 PolyComb抑制复合物2（PRC2）介导的H3K27三甲基化（H3K27ME3）假设这是DIPG肿瘤发生的驱动事件。蓬托是