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

• 批准号: 10078598
• 负责人: CHRISTOPHER VAKOC
• 金额: $ 55.22万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078598
• 关键词: Acute Myelocytic Leukemia; Address; Antineoplastic Agents; Area; Biochemical; Biochemical Genetics; Biological Assay; Biology; Bromodomain; CRISPR screen; CRISPR/Cas technology; Clinic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complex; Coupled; Deacetylase; Deacetylation; Dependence; Development; Diagnosis; Disease; Disease remission; Drug Combinations; Drug Targeting; Elements; Enhancers; Enzymes; Epigenetic Process; Evaluation; Exons; Generations; Genes; Genetic Screening; Genetic Transcription; Genome; Goals; Hematopoietic; Histones; Human; Hypersensitivity; In Vitro; KDM1A gene; Knowledge; Lead; Leukemic Cell; Lysine; Maintenance; Malignant Neoplasms; Measurement; Mediating; Mediator of activation protein; Membrane Proteins; Methylation; Methyltransferase; Modification; Molecular; Oncogenic; Oncology; Pathogenesis; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Protein Complex Subunit; Proteins; RNA interference screen; Reader; Refractory; Regimen; Relapse; Research; Resistance; Role; Scanning; Shapes; Source; Specificity; Surface; Techniques; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Validation; acute myeloid leukemia cell; cancer cell; chromatin protein; drug candidate; drug discovery; effective therapy; experimental study; genome-wide; in vivo; inhibitor/antagonist; innovative technologies; knock-down; leukemia; member; mouse model; novel therapeutics; p300/CBP-Associated Factor; predictive marker; prevent; programs; promoter; protein complex; protein protein interaction; recruit; response; small molecule; targeted treatment; therapeutic target; therapeutically effective; transcription factor; treatment response

Project Summary/Abstract The central goal of this project is to understand the role of BRD4 as an epigenetic vulnerability in acute myeloid leukemia. BRD4 is a bromodomain-containing reader of acetylated transcription factors and histones, and is a founding member of an emerging class of anti-cancer drug targets that function as transcriptional coactivators. While early stage clinical trials have revealed activity of BRD4 inhibitors in relapse-refractory AML patients, several challenges remain to successfully implement BRD4 inhibitors in the clinic. Following our successful effort over the past four years in revealing factors that function upstream and downstream of BRD4 to support AML maintenance, we now propose to address three fundamental gaps in our understanding of BRD4 as an epigenetic vulnerability in this disease. First, we seek to address one of the most perplexing issues underlying BRD4 as a therapeutic target, which is related to the source of specificity of transcriptional effects of BRD4 inhibitors. In Aim 1, we will test the hypothesis that the leukemogenic transcription factor MYB uses BRD4 as a coactivator to maintain the enhancer landscape in leukemia cells. The MYB-BRD4 interaction will be defined on a biochemical and genetic level, and will determine whether the linkage between these two regulators forms the basis for the gene-specific effects and the therapeutic index of BRD4 inhibitors in this disease. A second area of focus will be the Mediator complex, which is a 30-subunit protein complex that we have recently demonstrated is tethered to the genome by BRD4 at specific cis-elements. The intimate linkage between BRD4 and Mediator, together with the rich diversity of protein surfaces within this super-complex, leads us to evaluate in Aim 2 of this proposal whether discrete protein modules within Mediator might be required for AML maintenance, but dispensable for normal biology. This Aim will leverage the CRIPSR exon-scanning technique, which we recently developed to probe the essentiality of protein domains in sustaining cancer. We anticipate that a new generation of BRD4-like vulnerabilities will be present within this complex, and will be candidates for drug discovery. Finally, we seek to understand and overcome acquired resistance to BRD4 inhibition. Our domain-focused CRISPR screens have nominated the lysine deacetylase SIRT6 and lysine methyltransferase SUV420H2 as factors that modulate the sensitivity of AML cells to BRD4 inhibitors. In addition, we have identified LSD1 inhibition as a strategy for overcoming BRD4i resistance. In Aim 3, we will determine the function of these regulators in AML and their role in mediating the anti-leukemia response of BRD4 inhibition. This avenue of research may expose predictive biomarkers of BRD4 inhibitor responses, and potential avenues for overcoming resistance in the clinic. This research will continue to reveal principles of epigenetic perturbations in a therapeutic context, which can guide the development of next-generation therapeutics within this target class in oncology.

项目摘要/摘要 该项目的核心目标是了解BRD4作为急性髓样中的表观遗传脆弱性的作用 白血病。 BRD4是乙酰化转录因子和组蛋白的含溴结构域的读者，是一个 新兴类别的抗癌药物目标的创始成员 共激活因子。虽然早期临床试验揭示了BRD4抑制剂在复发性侵犯AML中的活性 患者，仍在诊所成功实施BRD4抑制剂的一些挑战。跟随我们 在过去四年中，成功的努力揭示了BRD4上游和下游功能的因素 为了支持AML维护，我们现在建议在理解BRD4时解决三个基本差距 作为这种疾病的表观遗传脆弱性。首先，我们试图解决最令人困惑的问题之一 基础BRD4作为治疗靶标，这与转录效应的特异性有关 BRD4抑制剂。在AIM 1中，我们将测试白血病转录因子MYB使用BRD4的假设 作为维持白血病细胞增强子景观的共激活因子。 MYB-BRD4相互作用将定义 在生化和遗传水平上，将确定这两个调节剂之间的联系是否形成 基因特异性作用和BRD4抑制剂的治疗指数的基础。第二 重点区域将是介体综合体，这是我们最近拥有的30-亚基蛋白复合物 BRD4在特定的顺式元素上通过BRD4束缚在基因组上。 BRD4之间的亲密联系 和调解人，加上这种超复合物中蛋白质表面的丰富多样性，使我们评估 在此提案的AIM 2中，AML是否可能需要调解器中的离散蛋白质模块 维护，但对于正常生物学来说是可分配的。这个目标将利用Cripsr外显子扫描技术， 我们最近开发的目的是探测蛋白质领域在维持癌症中的重要性。我们期待 在这个建筑群中将存在新一代的BRD4状漏洞，并将成为候选人 药物发现。最后，我们寻求理解并克服对BRD4抑制的获得的抵抗。我们的 以域为中心的CRISPR屏幕提名了赖氨酸脱乙酰基酶SIRT6和赖氨酸甲基转移酶 SUV420H2是调节AML细胞对BRD4抑制剂的敏感性的因素。此外，我们已经确定了 LSD1抑制是克服BRD4I抗性的策略。在AIM 3中，我们将确定这些功能 AML中的调节剂及其在介导BRD4抑制的抗白血病反应中的作用。这条途径 研究可能会暴露BRD4抑制剂反应的预测性生物标志物，以及克服的潜在途径 诊所的抵抗力。这项研究将继续揭示治疗中表观遗传扰动的原则 上下文，可以指导肿瘤学目标类别中下一代治疗剂的发展。