Role of PKC iota in metaplasia and initiation of pancreatic cancer

描述（由申请方提供）：胰腺导管腺癌（PDAC）是一种侵袭性、高致死性疾病，其特征是对常规治疗的极端耐药性。因此，有必要更好地了解驱动PDAC的信号通路，并确定分子靶向疗法治疗这种疾病的新的潜在靶点。K-ras原癌基因在绝大多数PDAC中突变，并且对于维持许多PDAC细胞系的转化表型是必需的。致癌性K-ras在PDAC的发生和发展中也起着关键作用。致癌K-ras在小鼠胰腺上皮中的表达诱导导管化生，随后形成癌前病变，小鼠胰腺上皮内瘤形成（mPanIN），并具有进展为PDAC的能力。这些观察结果强烈表明，致癌K-ras驱动胰腺癌发生的多步骤过程。然而，治疗靶向致癌K-ras的努力尚未成功，导致深入的努力，以确定更适合治疗干预的K-ras的关键下游效应子。我们已经发现蛋白激酶C1（PKC 1），在其他系统中致癌K-ras的已知下游效应物，在人胰腺肿瘤中高度过表达，并且高肿瘤PKC 1表达与患者存活率差相关。此外，我们已经发现PKC 1是表达致癌K-ras的PDAC细胞的转化生长和致瘤性所需的。PKC 1至少部分地通过致癌PKC 1-Rac1-MEK/ERK 1/2信号传导轴的激活来驱动PDAC细胞的转化生长。基于这些观察和我们的初步数据，我们假设PKC ι是致癌K-ras介导的PDAC启动和进展所必需的。我们进一步假设PKC 1/Rac1-MEK/ERK 1/2信号轴通过调节特定的促癌信号通路驱动胰腺癌发生。三个相互关联的具体目标是为了测试这些假设。1)探讨K-ras介导的化生所需的PKC ι调节信号机制。2)评估PKC ι在体内K-rasG12D介导的胰腺癌发生和mPanIN形成的启动中的作用。3)确定PKC i在K-rasG12D介导的PDAC中的作用。由于PDAC患者预后不良，NCI已将胰腺癌研究确定为优先资助项目。所提出的研究是高度转化的，并且与胰腺癌100%相关，目的是表征致癌K-ras介导的胰腺化生、mPanIN形成和进展为PDAC中对PKC i的需求。此外，我们将描述PKC ι参与致癌过程的分子机制。这些研究的重要性因目前存在治疗靶向PKC ι的能力而增强。因此，通过这些临床前研究获得的见解可能会转化为PDAC患者的新治疗策略。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly lethal disease marked by extreme resistance to conventional therapies. Thus, there is a need to better understand the signaling pathways that drive PDAC, and to identify new potential targets for molecularly-targeted therapies to treat this disease. The K-ras proto-oncogene is mutated in the vast majority of PDAC and is necessary for the maintenance of the transformed phenotype of many PDAC cell lines. Oncogenic K-ras also plays a critical role in the initiation and progression of PDAC. Expression of oncogenic K-ras in mouse pancreatic epithelium induces ductal metaplasia, followed by formation of preneoplastic lesions, mouse pancreatic intraepithelial neoplasias (mPanINs) with the ability to progress to PDAC. These observations strongly suggest that oncogenic K-ras drives a multi-step process of pancreatic carcinogenesis. However, efforts to therapeutically target oncogenic K-ras have not been successful, leading to intensive efforts to identify critical downstream effectors of K-ras that are more amenable to therapeutic intervention. We have found that protein kinase C iota (PKCι), a known downstream effector of oncogenic K-ras in other systems, is highly over-expressed in human pancreatic tumors, and that high tumor PKCι expression correlates with poor patient survival. Furthermore, we have found that PKCι is required for the transformed growth and tumorigenicity of PDAC cells expressing oncogenic K-ras. PKCι drives transformed growth of PDAC cells, at least in part, through activation of an oncogenic PKCι-Rac1- MEK/ERK1/2 signaling axis. Based on these observations, and our preliminary data, we hypothesize that PKCι is required for oncogenic K-ras-mediated PDAC initiation and progression. We further hypothesize that the PKCι/Rac1-MEK/ERK1/2 signaling axis drives pancreatic carcinogenesis by regulating specific pro-carcinogenic signaling pathways. Three interrelated specific aims are designed to test these hypotheses. 1) To dissect the PKCι-regulated signaling mechanisms required for K-ras-mediated metaplasia. 2) To assess the role of PKCι in K-rasG12D-mediated initiation of pancreatic carcinogenesis and mPanIN formation in vivo. 3) To determine the role of PKCι in K-rasG12D-mediated PDAC. Due to the poor prognosis of PDAC patients, the NCI has identified pancreatic cancer research as a funding priority. The proposed studies are highly translational and 100% relevant to pancreatic cancer, with the goal of characterizing the requirement for PKCι in oncogenic K-ras-mediated pancreatic metaplasia, mPanIN formation and progression to PDAC. In addition, we will characterize the molecular mechanism(s) by which PKCι contributes to the carcinogenic process. The significance of these studies is enhanced by the fact that the ability to therapeutically target PKCι currently exists. Thus, insights gained through these pre-clinical studies may be translated into new treatment strategies for PDAC patients.