Role of PKC iota in metaplasia and initiation of pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是一种侵袭性、高致死率的疾病，对常规治疗具有极强的耐药性。因此，有必要更好地了解驱动PDAC的信号通路，并确定分子靶向治疗这种疾病的新潜在靶点。K-ras原癌基因在绝大多数PDAC中发生突变，是维持许多PDAC细胞系转化表型所必需的。致癌基因K-ras在PDAC的发生和发展中也起着关键作用。在小鼠胰腺上皮中表达致癌性K-ras诱导导管化生，随后形成瘤前病变，小鼠胰腺上皮内瘤变（mPanINs），并有能力发展为PDAC。这些观察结果强烈表明，致癌的K-ras驱动了一个多步骤的胰腺癌发生过程。然而，针对致癌性K-ras的治疗努力尚未取得成功，这导致了对K-ras关键下游效应物的密集研究，这些效应物更适合治疗干预。我们发现蛋白激酶C - iota （PKC?）是其他系统中已知的致癌K-ras的下游效应物，在人类胰腺肿瘤中高度过表达，并且高肿瘤PKC?？表达与患者生存不良相关。此外，我们还发现PKC？是表达致癌K-ras的PDAC细胞转化生长和致瘤性所必需的。PKC吗?通过激活致癌PKC，至少在一定程度上驱动PDAC细胞的转化生长。- rac1 - MEK/ERK1/2信号轴。基于这些观察和我们的初步数据，我们假设PKC？是致癌的k -ras介导的PDAC启动和进展所必需的。我们进一步假设PKC？/Rac1-MEK/ERK1/2信号轴通过调节特定的促癌信号通路驱动胰腺癌的发生。设计了三个相互关联的具体目标来检验这些假设。1)剖析PKC？k -ras介导的化生所需的-调节信号机制。2)评估公正委员会的角色？k - rasg12d介导的胰腺癌起始和体内mPanIN的形成3)确定PKC的角色？k - rasg12d介导的PDAC由于PDAC患者预后不良，NCI已将胰腺癌研究确定为资助重点。拟议的研究具有高度的转译性，与胰腺癌100%相关，目的是表征PKC？在致癌的k -ras介导的胰腺化生，mPanIN的形成和PDAC的进展中。此外，我们将描述PKC？有助于致癌过程。这些研究的意义被以下事实所增强：治疗靶点PKC？目前尚不存在。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 (PKC?), a known downstream effector of oncogenic K-ras in other systems, is highly over-expressed in human pancreatic tumors, and that high tumor PKC??expression correlates with poor patient survival. Furthermore, we have found that PKC? is required for the transformed growth and tumorigenicity of PDAC cells expressing oncogenic K-ras. PKC? drives transformed growth of PDAC cells, at least in part, through activation of an oncogenic PKC?-Rac1- MEK/ERK1/2 signaling axis. Based on these observations, and our preliminary data, we hypothesize that PKC? is required for oncogenic K-ras-mediated PDAC initiation and progression. We further hypothesize that the PKC?/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 PKC?-regulated signaling mechanisms required for K-ras-mediated metaplasia. 2) To assess the role of PKC? in K-rasG12D-mediated initiation of pancreatic carcinogenesis and mPanIN formation in vivo. 3) To determine the role of PKC? 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 PKC? in oncogenic K-ras-mediated pancreatic metaplasia, mPanIN formation and progression to PDAC. In addition, we will characterize the molecular mechanism(s) by which PKC? contributes to the carcinogenic process. The significance of these studies is enhanced by the fact that the ability to therapeutically target PKC? currently exists. Thus, insights gained through these pre-clinical studies may be translated into new treatment strategies for PDAC patients.