Targeting Epigenomic Regulators at the Replication Fork in PDAC

针对 PDAC 复制叉处的表观基因组调节因子

• 批准号: 10366076
• 负责人: Gwen Lomberk
• 金额: $ 44.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366076
• 关键词: Address; Adenocarcinoma Cell; Applications Grants; Area; Bypass; CHEK1 gene; Cell Aging; Cell Cycle; Cell Cycle Stage; Cell Death; Cells; Chromatin Structure; Complex; DNA Damage; DNA biosynthesis; DNA damage checkpoint; DNA replication fork; Data; Data Reporting; Development; Disease; Epigenetic Process; Event; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomic DNA; Genomics; Germ-Line Mutation; Goals; Growth; In Vitro; Intelligence; Interphase; Investigation; KRAS2 gene; Knowledge; Licensing; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mission; Molecular; Oncogenes; Outcomes Research; Pain; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Predisposition; Process; Proteins; Role; S phase; Scientific Advances and Accomplishments; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; base; cancer cell; cancer initiation; cell growth; epigenome; epigenomics; histone methyltransferase; improved; in vivo; individual patient; inhibitor; inhibitor therapy; insight; novel; novel therapeutics; pancreatic cancer patients; patient subsets; prevent; public health relevance; repaired; replication stress; research clinical testing; response; stress tolerance; therapy development; treatment strategy; tumor; tumor progression; tumorigenesis; whole genome

Pancreatic adenocarcinoma (PDAC) remains a therapeutic challenge, making the identification of new targets and development of novel treatment strategies for this disease of paramount importance. Our LONG-TERM GOAL is to advance context-dependent, mechanism-based paradigms for the improved use of epigenomic inhibitors in cancer. Epigenomic machinery, and hence their inhibitors, are typically only considered within the context of their actions in gene expression, or interphase, even though they are operational during different stages of the cell cycle. During the process of DNA replication, for instance, not only is the entire genome replicated, but the accompanying chromatin structure is duplicated as well. Thus, conceptually, DNA replication represents a vulnerable moment for challenging genomic and epigenomic integrity, which relies heavily on the proper functioning of the S-phase DNA replication checkpoint (DRC) and DNA damage response (DDR) as critical components of this process. Early in tumorigenesis, higher proliferation rates driven by activated oncogenes, such as KRAS, trigger replication stress (RS), which if not tolerated causes cell senescence or death. RS tolerance, consequently, becomes vital to tumor progression, yet the underlying mechanisms remain poorly understood. Here, we will test the CENTRAL HYPOTHESIS that the epigenomic regulator G9a promotes RS tolerance in PDAC via a mechanism which involves interactions with S-phase DRC-DDR pathways, representing actionable vulnerabilities for therapeutics. Completion of these studies will significantly advance the field by: 1. revealing mechanisms by which G9a functions in the tolerance to oncogene-induced RS, a key understudied event in tumorigenesis, 2. providing novel mechanistic insight into how G9a-mediated function in DDR signaling protects replication fork integrity to offer additional targeting strategies for the subset of patients with inherent DDR deficiencies, and 3. leveraging the function of epigenetic regulators during oncogene-driven RS as a mechanistic opportunity to synergize with RS- enhancing drugs, such as DDR-inhibitors. In summary, we seek to extend our studies on new mechanisms that represent previously unrecognized actionable vulnerabilities for cancer cells. We are optimistic that the outcome of this research will impact planning for future clinical testing of therapies that may share similar mechanisms to offer much-needed, novel treatments for PDAC.

胰腺癌（PDAC）仍然是一个治疗挑战，需要确定新的靶点 开发针对这种疾病的新治疗策略至关重要。我们的长期目标 目标是推进依赖于环境、基于机制的范式，以改进表观基因组学的使用 癌症抑制剂。表观基因组机制及其抑制剂通常仅在以下范围内被考虑： 它们在基因表达或间期中的作用背景，即使它们在不同的时期运作 细胞周期的阶段。例如，在 DNA 复制过程中，不仅整个基因组 复制，但伴随的染色质结构也复制。因此，从概念上讲，DNA 复制代表了挑战基因组和表观基因组完整性的脆弱时刻，这依赖于 很大程度上取决于 S 期 DNA 复制检查点 (DRC) 的正常运作和 DNA 损伤 响应（DDR）作为该过程的关键组成部分。肿瘤发生早期，增殖率较高 由激活的癌基因（例如 KRAS）驱动，会触发复制应激 (RS)，如果不耐受，会导致复制应激 (RS) 细胞衰老或死亡。因此，RS 耐受性对于肿瘤进展至关重要，但潜在的 机制仍知之甚少。在这里，我们将检验表观基因组的中心假设 调节器 G9a 通过与 S 相相互作用的机制促进 PDAC 中的 RS 耐受性 DRC-DDR 途径，代表治疗方法的可操作漏洞。完成这些研究将 通过以下方式显着推进该领域的发展： 1. 揭示 G9a 在耐受性中发挥作用的机制 癌基因诱导的 RS，肿瘤发生中一个关键的、尚未研究的事件，2. 提供了新的机制见解 DDR 信号传导中 G9a 介导的功能如何保护复制叉完整性以提供额外的靶向 针对具有先天性 DDR 缺陷的患者子集的策略，以及 3. 利用 表观遗传调节剂在癌基因驱动的RS过程中作为与RS协同作用的机械机会 增强药物，例如 DDR 抑制剂。总之，我们寻求扩展对新机制的研究 这代表了以前未被认识到的癌细胞的可操作弱点。我们乐观地认为 这项研究的结果将影响未来可能具有相似特征的疗法的临床测试计划 为 PDAC 提供急需的新颖治疗方法的机制。