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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：
10654155
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/10654155
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 Expression Profile Gene Silencing Generations Genes Genetic Genetic Engineering Genetic Transcription Glioma Goals H3 K27M mutation 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 efficacious treatment epigenome experimental study genome-wide improved in vivo inhibitor inhibitor therapy insight mortality mouse model mutant neoplastic cell 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

弥散特征组蛋白替代水平和通过分析表观基因组