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: 10596590
• 负责人: Gwen Lomberk
• 金额: $ 44.46万
• 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/10596590
• 关键词: Adenocarcinoma Cell; Applications Grants; Area; Bypass; CHEK1 gene; Cell Aging; Cell Cycle; Cell Cycle Stage; Cell Death; Cells; Chromatin Structure; Combined Modality Therapy; Compensation; 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; Proliferating; Proteins; Role; S phase; Scientific Advances and Accomplishments; Signal Induction; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; cancer cell; cancer initiation; cell growth; coping; 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; synergism; 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，使新的靶点的鉴定 和发展新的治疗策略对这种疾病至关重要。我们的长期 目标是推进上下文相关的，基于机制的范例，以改善表观基因组的使用。 癌症的抑制剂。表观基因组机制，因此其抑制剂，通常只考虑在 它们在基因表达或间期的作用背景，即使它们在不同的时期都是可操作的。 细胞周期的各个阶段。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被复制。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， 严重影响S期DNA复制检查点（DRC）的正常功能和DNA损伤 复员方案是这一进程的关键组成部分。在肿瘤发生的早期， 由激活的癌基因驱动，如KRAS，触发复制应激（RS），如果不能耐受， 细胞衰老或死亡。因此，RS耐受性对肿瘤进展至关重要，但潜在的免疫耐受性可能是肿瘤发生的关键因素。 机制仍然知之甚少。在这里，我们将测试中心假设，即表观基因组 调节因子G9a通过与S期相互作用的机制促进PDAC中的RS耐受 DRC-DDR途径，代表治疗的可操作漏洞。完成这些研究将 通过以下方式显著推进该领域：1。揭示了G9a在耐受性中发挥作用的机制， 癌基因诱导的RS，一个关键的未充分研究的事件在肿瘤发生，2。提供了新的机械洞察力， DDR信号传导中G9a介导的功能如何保护复制叉的完整性以提供额外的靶向 针对具有固有DDR缺陷的患者子集的策略，以及3.发挥以下职能： 在癌基因驱动的RS过程中，表观遗传调节因子作为与RS协同作用的机制机会， 增强药物，如DDR抑制剂。总之，我们寻求扩展我们对新机制的研究， 这代表了以前未被认识到的癌细胞的可操作的弱点。我们看好 这项研究的结果将影响未来临床试验的计划， 为PDAC提供急需的新型治疗机制。