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Role of RBBP4/p300 Complex in Recovery from therapy induced DNA damage in glioblastoma

RBBP4/p300 复合物在胶质母细胞瘤治疗诱导的 DNA 损伤恢复中的作用

基本信息

批准号：
10266757
负责人：
Gaspar Julius Kitange
金额：
$ 14.71万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-19 至 2021-12-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266757
关键词：
Acetylation Animal Model BARD1 gene BRCA1 gene BRD2 gene Binding Biological Assay Bromodomain Cells Chemotherapy and/or radiation Chromatin Clinical Clinical Trials Co-Immunoprecipitations Complex DNA Damage DNA Double Strand Break DNA Methylation DNA Repair DNA replication fork Data Disease EP300 gene Enhancers Epigenetic Process Failure Family Family member Gene Expression Genes Genetic Genetic Enhancer Element Genetic Transcription Glioblastoma Goals Histone Acetylation Histones Impairment Lesion Ligation Link Mediating Modeling Nature Newly Diagnosed Normal Cell Normal tissue morphology Oncology PARP inhibition Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Play Process Promoter Regions Protein Family Proteins RNA Polymerase II Radiation Reader Recovery Recurrence Recurrent disease Regulation Regulatory Pathway Reporting Research Retinoblastoma Role Series Tertiary Protein Structure Testing Therapeutic Time Tumor Tissue adduct aggressive therapy base c-myc Genes chemotherapy clinically relevant cytotoxicity design efficacy testing gene product glioma cell line histone acetyltransferase homologous recombination in vivo inhibitor/antagonist insight knock-down novel novel therapeutic intervention patient derived xenograft model promoter protein expression protein function recruit repaired research clinical testing response small hairpin RNA temozolomide tool transcription factor tumor

项目摘要

PROJECT SUMMARY Temozolomide (TMZ) chemotherapy is a key component of treatment for patients with newly diagnosed glioblastoma (GBM) and provides clinically meaningful survival benefits. Cytotoxicity from TMZ results from failure to repair TMZ-induced DNA methylation adducts. During replication, these lesions ultimately result in replication fork collapse associated with DNA double strand breaks that are critically repaired by homologous recombination (HR). In this context, we recently discovered that retinoblastoma binging protein 4 (RBBP4) functions in a complex with histone acetyltransferase p300 (p300) as a epigenetic writer to key DNA repair processes including six key HR genes (RAD50, BRCA1, BARD1 BRIP1 FIGNL1, and RAD51) that play different roles in HR pathway. Specifically, knockdown of either RBBP4 or p300 in glioma cell lines and GBM patient-derived xenograft (PDX) models results in marked suppression of these six gene products, impaired HR activity associated with enhanced sensitivity to PARP inhibitors, and dramatically enhanced sensitivity to TMZ in animal models. Downstream of RBBP4/p300 complex, bromodomain and extraterminal domain (BET) family members (BRD2, BRD3, BRD4) function as key readers of p300-mediated acetylation marks to drive gene expression. Based on this and our preliminary data, we hypothesize that the RBBP4/p300/BRD axis is a key regulator of HR efficiency and is a promising pharmacologic strategy for developing a robust, novel, TMZ- sensitizing strategy. There are both p300- and dual p300/BET-inhibitors now entering clinical testing in oncology, which highlight the importance of fully understanding how this complex functions to regulate DNA repair. We will explore this concept in a series of three specific aims: Aim 1: Define the role of RBBP4/p300 in regulation of HR genes. We will extend our initial observations in GBM43 to define the regulation of HR genes across multiple GBM models by this complex. Aim 2: Evaluate the impact of RBBP4/p300 on DNA repair proficiency. We hypothesize that coordinated suppression of multiple HR genes associated with disruption of RBBP4/p300/BET function results in profound HR suppression and TMZ sensitizing effects as compared to modulation of only one component of HR. Aim 3: Define the impact of targeting the p300/BRD4 axis on therapy response in GBM We will test the efficacy of p300 and p300/BET inhibitors alone and in combination with TMZ in PDX models. Ultimately, these studies are designed to provide a strong rationale to pursue these inhibitors in clinical trials for GBM.

项目总结