Project 4: Transcriptional Coactivators and Enhancers in Human Cancer

项目摘要--项目4 新出现的证据表明，转录共激活因子和增强子元件起着核心作用 在人类癌症的发病机制中起着重要作用。项目4中概述的研究将开发转录 辅活化子作为支持癌细胞异常能力的蛋白质，从而揭示了一类新的 肿瘤学中的表观遗传药物靶点。本研究将探讨SWI/SNF和TFIID共激活因子的作用 复合体在急性髓系白血病(AML)发病机制中的作用并将确定辅活化子的新角色 支持晚期胰腺导管腺癌(PDA)的进展。这样做的第一个目的是 提案将分析BRD9溴域的化学抑制剂的抗白血病效果，这些化合物是 我们与勃林格-英格尔海姆公司合作开发的新化合物。这项工作的主要目标是 研究将开发药物组合，以增强抑制BRD9对AML的治疗效果。 这将包括使用CRISPR扫描和以领域为重点的CRISPR筛查，这是最近推出的 开发了基因工具，可以对内源性蛋白质复合体进行深入的机制研究，并 揭示药物再利用的机会。这项研究具有直接激励临床研究的潜力。 急性髓系白血病患者人群中的新药物组合。第二个目标是开发TAF12/TFIID复合体 作为急性髓系白血病的一种新的依赖性，并揭示其支持癌基因介导的潜在机制 白血病转化。这还将包括确定直接化学抑制这一过程的适当途径 复杂性，这一目标在癌症表观遗传学领域尚未实现，主要是由于我们的 对TFIID如何支持癌症发病机制的了解不完全。项目4的第三个目标将是 理解翻译后作者、读者和擦除者对核小体结构的调制 组蛋白标记可能赋予PDA细胞发生转移的能力。这将包括域- 集中CRISPR筛查小鼠模型中允许远端转移的染色质调节因子 掌上电脑。由于早期转移是导致动脉导管未闭患者高死亡率的主要原因，这项研究可能 极大地影响了我们对这种疾病致命形式的基本理解，并可能 揭示了这种恶性肿瘤的表观遗传药物靶点。重要的是，项目4中概述的研究将提供 对支持AML和PDA的转录机制进行深入的机制研究，这将依赖于 广泛使用表观基因组学工具(例如，基于芯片序列的增强子活性测量)，以及生化 接近了。项目4还将与其他项目和核心进行广泛合作，以进行评估 恶性细胞的分子机制和体内生物学。这项基础研究将揭示小说 致命恶性肿瘤的脆弱性，这可能为治疗提供新的途径。

PROJECT SUMMARY - PROJECT 4 Emerging evidence has implicated transcriptional coactivators and enhancer elements as having a central role in the pathogenesis of human cancer. The research outlined in Project 4 will develop transcriptional coactivators as proteins that support the aberrant capabilities of cancer cells, thus revealing a novel class of epigenetic drug targets in oncology. This research will explore the role of SWI/SNF and TFIID coactivator complexes in the pathogenesis of Acute Myeloid Leukemia (AML) and will identify novel roles for coactivators in supporting the progression of late-stage Pancreatic Ductal Adenocarcinoma (PDA). The first Aim of this proposal will analyze the anti-leukemia effects of chemical inhibitors of the bromodomain of BRD9, which are novel compounds we generated in collaboration with Boehringer-Ingelheim. The major objective of this research will be to develop drug combinations that augment the therapeutic effects of BRD9 inhibition in AML. This will include use of CRISPR-scanning and domain-focused CRISPR screening, which are recently developed genetic tools to allow deep mechanistic investigation of endogenous protein complexes and to reveal opportunities for drug repurposing. This research has a direct potential to motivate clinical studies of novel drug combinations in AML patient populations. The second Aim will develop the TAF12/TFIID complex as a novel dependency in AML and reveal its underlying mechanism in supporting oncogene-mediated leukemic transformation. This will also include identifying suitable routes for direct chemical inhibition of this complex, an objective that has yet to be achieved in the cancer epigenetics field, largely owing to our incomplete understanding about how TFIID supports cancer pathogenesis. The third Aim of Project 4 will be to understand how modulation of nucleosome structure by writers, readers, and erasers of post-translational histone marks might endow PDA cells with the capacity to undergo metastasis. This will include domain- focused CRISPR screening to interrogate chromatin regulators that allow distal metastasis in mouse models of PDA. Since early metastasis is a major contributor to the high mortality of PDA patients, this research may significantly impact our basic understanding of the lethal form of this disease, and carries the potential for revealing epigenetic drug targets for this malignancy. Importantly, the research outlined in Project 4 will provide a deep mechanistic investigation of transcriptional mechanisms that support AML and PDA, which will rely on extensive use of epigenomic tools (e.g. ChIP-seq-based measurement of enhancer activity), and biochemical approaches. Project 4 will also feature extensive collaborations with the other Projects and Cores to evaluate molecular mechanisms and in vivo biology of malignant cells. This basic research will reveal novel vulnerabilities in lethal malignancies, which could provide new routes for therapy.