Targeting of Krüppel-like Factor 5 (KLF5) in Pancreatic Ductal Adenocarcinoma

Krüppel 样因子 5 (KLF5) 在胰腺导管腺癌中的靶向作用

• 批准号: 10607399
• 负责人: Patrick Cunniff
• 金额: $ 4.77万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2026-02-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607399
• 关键词: Acinar Cell; Acute; Address; Adult; Binding; Biochemical; Biological Sciences; Biology; Cancer Cell Growth; Cell Proliferation; Cells; Chemoresistance; Chromatin; Clinical; Complementary DNA; Complex; Cytotoxic Chemotherapy; Data; Dependence; Development; Diagnosis; Environment; Epigenetic Process; Epithelium; Gene Expression Regulation; Genes; Genetic Screening; Genetic Transcription; Genetic study; Genome; Goals; Growth; Homeostasis; Human; In Vitro; Individual; Inflammation; Intestines; Investigation; KRAS oncogenesis; Knowledge; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Mass Spectrum Analysis; Mentorship; Modeling; Molecular; Mus; Mutation; Oncogenic; Output; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatitis; Patients; Process; Prognosis; Proteins; Regenerative capacity; Reporter; Research; Resources; Role; Schools; Serpins; Shapes; Survival Rate; Therapeutic; Therapeutic Index; Tissues; Training Programs; Transcription Coactivator; Transgenic Mice; Up-Regulation; acute pancreatitis; anticancer research; cancer cell; cancer type; cell growth; drug development; drug discovery; effective therapy; epigenome; epigenomics; fitness; improved; innovation; mouse genetics; mouse model; multiple omics; new therapeutic target; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic tumorigenesis; precursor cell; protein protein interaction; skills; standard of care; stem cell self renewal; stem cells; targeted treatment; therapeutic target; transcription factor; tumor; tumorigenesis

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly tumor type with one-year and five-year survival rates of less than 20% and 10% respectively. This project seeks to explore the potential for Krüppel-like factor 5 (KLF5) to be a novel therapeutic target in PDAC. The proposed research leverages three key discoveries. First, high-throughput genetic screening has revealed that PDAC human cancer cells are selectively sensitive to KLF5 inactivation. Second, KLF5 expression is low in normal pancreas tissue, but KLF5 is upregulated during pancreatitis and supports the proto-oncogenic function of Kras in this context. Third, mouse genetic studies indicate that normal intestinal stem-cell self-renewal continues in the absence of Klf5. These data together suggest KLF5 has a wide therapeutic index in PDAC. However, KLF5 is a difficult target for classical drug discovery approaches, largely due to our limited understanding of protein-protein interactions which support KLF5 function. This project will address two major gaps in our understanding of KLF5 in PDAC. It will evaluate whether targeting KLF5 interactions disrupts KLF5 function, and it will explore how KLF5 contributes to proto- oncogenesis of PDAC precursor cells. An integrated high-throughput reporter screen and mass spectrometry analysis has illustrated that several KLF5 coactivators also bind KLF5. These coactivators will be deeply investigated to reveal the mechanisms of their interactions with KLF5. This investigation will highlight whether KLF5-coactivator interactions are critical both for KLF5 transcriptional activity and for PDAC cell fitness (Aim 1). The overall goal of this aim is to understand if these interactions can be exploited to acutely target KLF5 activity in PDAC. This will inform the potential for the advancement of KLF5 as a targeted therapy. In addition, pancreatitis promotes an aberrant proto-oncogenic epigenetic landscape, and also leads to Klf5 upregulation. Using a transgenic mouse model, the function of Klf5 in normal and inflamed pancreatic tissue will be interrogated. Specifically, this investigation will determine if Klf5 supports the aberrant epigenic profile induced by pancreatitis (Aim 2). The overall goal of this aim will be to determine if Klf5 has an active role in shaping the genome of PDAC progenitor cells. This might explain why PDAC is selectively sensitive to KLF5 deletion, while KLF5 is entirely dispensable in normal pancreatic homeostasis. The required skills and knowledge to carry out these two aims will be supported by sponsor Dr. Chris Vakoc and co-sponsor Dr. David Tuveson, in addition to the Cold Spring Harbor Laboratory School of Biological Sciences. The mentorship and environment at Cold Spring Harbor Laboratory will provide all of the necessary resources for a tailored training program to effectively develop the applicant into an independent experimentalist, analyst, and communicator of gene regulation biology and cancer research.

项目摘要 胰腺导管腺癌（PDAC）是一种非常致命的肿瘤类型，一年和五年 生存率分别小于20％和10％。该项目旨在探索类似克鲁佩尔的潜力 因子5（KLF5）是PDAC中新型治疗靶标。拟议的研究利用了三个关键 发现。首先，高通量基因筛查表明PDAC人类癌细胞有选择性 对KLF5失活敏感。其次，在正常胰腺组织中KLF5表达低，但KLF5为 在这种情况下，胰腺炎期间上调，并支持KRAS的原始功能。第三，鼠标 通用研究表明，在没有KLF5的情况下，正常的肠干自我更新会继续。这些数据 共同表明KLF5在PDAC中具有广泛的治疗指数。但是，KLF5是经典的困难目标 药物发现方法，主要是由于我们对支持蛋白质 - 蛋白质相互作用的有限理解 KLF5功能。该项目将解决我们对PDAC KLF5的理解的两个主要差距。它将评估 靶向KLF5相互作用是否会破坏KLF5的功能，它将探讨KLF5如何促进原始 PDAC前体细胞的肿瘤发生。 集成的高通量记者屏幕和质谱分析表明，几个KLF5 共激活因子还结合KLF5。这些共激活因子将经过深入研究，以揭示其机制 与KLF5的相互作用。这项投资将强调KLF5连续激活者的互动是否至关重要 KLF5转录活性和PDAC细胞适应性（AIM 1）。这个目标的总体目标是了解是否存在 可以将这些相互作用探索到PDAC中急性靶向KLF5活性。这将为可能的潜力 KLF5作为目标疗法的进步。 此外，胰腺炎还促进了异常的原始性表观遗传景观，也导致KLF5 上调。使用转基因小鼠模型，KLF5在正常和发炎的胰腺组织中的功能将 审问。特别是，这项投资将确定KLF5是否支持引起异常的表观遗传概况 由胰腺炎（AIM 2）。这个目标的总体目标是确定KLF5在塑造该klf5是否具有积极作用 PDAC祖细胞的基因组。这可能解释了为什么PDAC对KLF5删除有选择性敏感，而 KLF5在正常的胰腺体内平衡中完全可分配。 发起这两个目标的所需技能和知识将由赞助商Chris Vakoc博士和 戴维·图维森（David Tuveson）博士的共同赞助人，除了冷泉港实验室生物科学学院外。 冷春港实验室的精通和环境将提供所有必要的资源 对于量身定制的培训计划，可以有效地将申请人发展为独立的实验者，分析师， 以及基因调节生物学和癌症研究的通信。