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

项目摘要 胰腺导管腺癌（PDAC）是一种极其致命的肿瘤类型， 存活率分别低于20%和10%。该项目旨在探索类似Krüppel的潜力 第5因子（KLF 5）是PDAC治疗的新靶点。该研究利用了三个关键 发现。首先，高通量遗传筛选已经揭示了PDAC人类癌细胞选择性地 对KLF 5失活敏感。第二，KLF 5在正常胰腺组织中表达较低，但KLF 5在正常胰腺组织中表达较低。 在胰腺炎期间上调，并在此背景下支持Kras的原癌基因功能。三、鼠标 遗传研究表明，正常的肠干细胞自我更新在Klf 5缺失的情况下继续。这些数据 提示KLF 5在PDAC中具有广泛的治疗指数。然而，KLF 5是经典的靶点， 药物发现方法，很大程度上是由于我们对蛋白质-蛋白质相互作用的理解有限， KLF 5功能。这个项目将解决我们对PDAC中KLF 5的理解中的两个主要差距。它将评估 靶向KLF 5相互作用是否会破坏KLF 5的功能，并将探讨KLF 5如何有助于原核表达。 PDAC前体细胞的肿瘤发生。 整合的高通量报告筛选和质谱分析表明，几个KLF 5 辅活化剂也结合KLF 5。这些共活化剂将被深入研究，以揭示其作用机制。 与KLF 5的相互作用这项研究将突出KLF 5-辅激活剂的相互作用是否是至关重要的， KLF 5转录活性和PDAC细胞适应性（目的1）。这一目标的总体目标是了解， 这些相互作用可用于在PDAC中急性靶向KLF 5活性。这将为潜在的 KLF 5作为靶向治疗的进展。 此外，胰腺炎促进异常的原癌基因表观遗传景观，也导致Klf 5 上调。使用转基因小鼠模型，Klf 5在正常和炎症胰腺组织中的功能将被发现。 被审问具体地，该研究将确定Klf 5是否支持诱导的异常表观遗传特征。 胰腺炎（Aim 2）。这一目标的总体目标是确定Klf 5是否在塑造 PDAC祖细胞的基因组。这可能解释了为什么PDAC对KLF 5缺失选择性敏感， KLF 5在正常胰腺内稳态中完全不起作用。 实现这两个目标所需的技能和知识将得到赞助商Chris Vakoc博士的支持， 共同赞助人大卫Tuveson博士，除了生物科学的冷泉港实验室学校。 冷泉港实验室的指导和环境将提供所有必要的资源 一个量身定制的培训计划，以有效地发展申请人成为一个独立的实验，分析师， 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.