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

项目总结 摘要胰腺导管腺癌是一种极具致命性的肿瘤类型，其发病时间为一年和五年。 存活率分别低于20%和10%。这个项目试图探索类似Krüppel的潜力 因子5(KLF5)有望成为PDAC治疗的新靶点。这项拟议的研究利用了三个关键 发现。首先，高通量基因筛查显示，PDAC人类癌细胞具有选择性 对KLF5失活敏感。第二，KLF5在正常胰腺组织中低表达，但KLF5在正常胰腺组织中低表达 在胰腺炎期间表达上调，并在此背景下支持Kras的原癌功能。第三，鼠标 遗传学研究表明，在缺乏KLF5的情况下，正常的肠道干细胞自我更新仍在继续。这些数据 提示KLF5对PDAC有广泛的治疗指标。然而，KLF5对于古典音乐来说是一个困难的目标 药物发现方法，很大程度上是因为我们对蛋白质-蛋白质相互作用的有限理解 KLF5函数。这个项目将解决我们在PDAC中对KLF5的理解中的两个主要差距。它将评估 靶向KLF5的相互作用是否会扰乱KLF5的功能，并将探索KLF5如何促进原生生物- PDAC前体细胞的致癌作用。 集成的高通量报告屏幕和质谱分析表明，几个KLF5 共激活子也结合KLF5。这些共激活剂将被深入研究，以揭示其作用机制 与KLF5的相互作用。这项研究将强调KLF5-辅激活子相互作用是否对 KLF5转录活性和PDAC细胞适合性(目标1)。这个目标的总体目标是了解 这些相互作用可以被用来准确地靶向PDAC中的KLF5活性。这将通知潜在的 KLF5作为靶向治疗的研究进展 此外，胰腺炎促进了一种异常的原癌基因表观遗传格局，也导致了KLF5 上调。利用转基因小鼠模型，KLF5在正常和炎症的胰腺组织中的功能将 被审问。具体地说，这项研究将确定KLF5是否支持由 胰腺炎(目标2)。这一目标的总体目标将是确定KLF5是否在塑造 PDAC祖细胞基因组。这可能解释了为什么PDAC对KLF5缺失选择性敏感，而 在正常的胰腺内稳态中，KLF5是完全可有可无的。 实现这两个目标所需的技能和知识将由赞助商Chris Vakoc博士和 除了冷泉港生物科学实验学院，大卫·图夫森博士也是联合赞助商。 冷泉港实验室的指导和环境将提供所有必要的资源 提供量身定制的培训计划，有效地将申请者培养成一名独立的实验者、分析员、 基因调控生物学和癌症研究的传播者。

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.