BET bromodomain inhibition as targeted therapy in acute myeloid leukemia

BET 溴结构域抑制作为急性髓系白血病的靶向治疗

基本信息

批准号：
8635318
负责人：
CHRISTOPHER VAKOC
金额：
$ 53.26万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635318
关键词：
Accounting Acute Myelocytic Leukemia Address Animal Model Antineoplastic Agents Biochemical Biochemical Genetics Biological Assay Bromodomain Cells ChIP-seq Chromatin Clinical Clinical Trials Complex Dependency Development Disease Disease Progression Drug Targeting Enzymes Epigenetic Process Experimental Leukemia FDA approved Future Gene Components Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Hematopoietic Human In Vitro Individual Maintenance Malignant - descriptor Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Methodology Modeling Modification Molecular Normal tissue morphology Oncogenes Oncogenic Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Pharmacologic Substance Property Proteins Proteomics Reading Recruitment Activity Regimen Regulation Regulator Genes Research Resistance Role Tertiary Protein Structure Therapeutic Therapeutic Index Toxic effect Transcriptional Regulation Work base cancer cell chemotherapy drug candidate epigenomics improved in vivo inhibitor/antagonist insight leukemia member mouse model mutant novel patient population pre-clinical programs protein complex protein protein interaction public health relevance screening small hairpin RNA small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The central goal of this project is to understand the role of BRD4 as a therapeutic target in acute myeloid leukemia. As a regulator of chromatin, BRD4 is a member of an emerging class of anti-cancer drug targets for which little is understood of its therapeutically-relevant molecular function. This proposal seeks to address this issue by identifying the critical biochemical mechanism employed by BRD4 in leukemia cells that accounts for its desirable properties as a therapeutic target. This will include evaluating which regions of BRD4 are most crucial for its disease-related functions, as well as identifying the key protein constituents of the BRD4 complex that are necessary for leukemia maintenance in experimental mouse models. Efforts will also be made to identify effective therapeutic combinations that can synergize with BRD4 inhibitors to suppress leukemia progression in preclinical leukemia models. This project will rely on integrative approaches, including biochemical, genetic, proteomic, and epigenomic strategies. This research will make extensive use of genetically-engineered mouse models of chemotherapy-resistant leukemia, which will be used to evaluate the in vivo efficacy of various therapeutic manipulations of BRD4 or components of its protein complex. In summary, the long-term goal of this research will be to maximize the clinical benefit of targeting BRD4 in leukemia through an understanding of the detailed mechanism of how this protein works as a regulator of chromatin state.

描述（由申请人提供）：该项目的中心目标是了解 BRD4 作为急性髓系白血病治疗靶点的作用。作为染色质的调节剂，BRD4 是一类新兴抗癌药物靶点的成员，对其治疗相关的分子功能知之甚少。该提案旨在通过确定 BRD4 在白血病细胞中所采用的关键生化机制来解决这个问题，该机制解释了其作为治疗靶标的理想特性。这将包括评估 BRD4 的哪些区域对其疾病相关功能最重要，以及确定实验小鼠模型中维持白血病所必需的 BRD4 复合物的关键蛋白质成分。还将努力寻找能够与 BRD4 抑制剂协同作用的有效治疗组合，以抑制临床前白血病模型中的白血病进展。该项目将依赖于综合方法，包括生化、遗传、蛋白质组和表观基因组策略。这项研究将广泛使用化疗耐药性白血病的基因工程小鼠模型，该模型将用于评估 BRD4 或其蛋白质复合物成分的各种治疗操作的体内功效。总之，这项研究的长期目标是通过了解 BRD4 作为染色质状态调节剂的详细机制，最大限度地提高靶向 BRD4 在白血病中的临床益处。