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：
9884955
负责人：
Gaspar Julius Kitange
金额：
$ 36.4万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9884955
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 Xenograft Model Xenograft procedure 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 therapeutics 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.

项目摘要替莫唑胺（TMZ）化学疗法是新诊断患者治疗的关键组成部分胶质母细胞瘤（GBM），并提供临床上有意义的生存益处。 TMZ的细胞毒性来自无法修复TMZ诱导的DNA甲基化加合物。在复制过程中，这些病变最终导致复制叉塌陷与DNA双链断裂相关重组（HR）。在这种情况下，我们最近发现视网膜母细胞瘤蛋白4（RBBP4）用组蛋白乙酰转移酶P300（P300）作为表观遗传学作者进行关键DNA修复的功能包括六个关键HR基因（RAD50，BRCA1，BARD1 BRIP1 FIGNL1和RAD51）的过程在人力资源途径中的不同角色。具体而言，在神经胶质瘤细胞系和GBM中敲低RBBP4或P300 患者衍生的异种移植（PDX）模型导致对这六种基因产物的明显抑制受损与增强对PARP抑制剂的敏感性相关的HR活性，并显着增强对动物模型中的TMZ。 RBBP4/P300复合物，溴结构域和外部域（BET）的下游家庭成员（BRD2，BRD3，BRD4）作为P300介导的乙酰化标记的关键读取器的功能基因表达。基于此和我们的初步数据，我们假设RBBP4/P300/BRD轴是一个人力资源效率的关键调节剂，是一种有前途的药理策略，用于开发健壮的新型，TMZ- 敏感策略。现在有P300和双P300/BET抑制剂正在进入临床测试肿瘤学强调了完全了解该复合物如何调节DNA的重要性维修。我们将在一系列特定目标中探讨这个概念： AIM 1：定义RBBP4/P300在调节HR基因中的作用。我们将在 GBM43通过该复合物定义了多个GBM模型的HR基因的调节。 AIM 2：评估RBBP4/P300对DNA修复能力的影响。我们假设该协调抑制与RBBP4/p300/BET功能有关的多个HR基因导致深刻的与仅对HR的一个组成部分的调制相比，HR抑制和TMZ敏化效应。 AIM 3：定义靶向P300/BRD4轴对GBM治疗反应的影响，我们将测试 p300和p300/BET抑制剂的功效和PDX模型中的TMZ的功效。最终，这些研究旨在为GBM的临床试验中追求这些抑制剂提供强大的理由。