Role of PKC iota in metaplasia and initiation of pancreatic cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种侵袭性的、高度致命的疾病，其特点是对传统疗法具有极强的耐药性。因此，有必要更好地了解驱动PDAC的信号通路，并为治疗这种疾病的分子靶向治疗确定新的潜在靶点。K-ras原癌基因在绝大多数PDAC中发生突变，是维持许多PDAC细胞转化表型所必需的。致癌K-ras在PDAC的发生和发展中也起着关键作用。癌基因K-ras在小鼠胰腺上皮细胞中的表达诱导导管上皮化生，继而形成癌前病变，小鼠胰腺上皮内瘤变(MPanINs)具有进展为PDAC的能力。这些观察结果强烈表明致癌的K-ras基因驱动了胰腺癌发生的多步骤过程。然而，治疗靶向致癌K-ras的努力并不成功，导致人们加紧努力寻找更适合治疗干预的K-ras关键下游效应因子。我们已经发现，在其他系统中已知的致癌K-ras下游效应蛋白激酶C(PKC？)在人胰腺肿瘤中高度过度表达，并且高表达与患者的生存不良有关。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？至少部分地通过激活致癌的PKC？-rac1-MEK/ERK1/2信号轴来推动PDAC细胞的转化生长。基于这些观察结果和我们的初步数据，我们假设PKC？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？/rac1-MEK/ERK1/2信号轴通过调节特定的致癌信号通路来驱动胰腺癌的发生。我们设计了三个相互关联的具体目标来检验这些假设。1)剖析K-ras介导的化生所需的PKC调节的信号机制。2)评估PKC的作用？在K-RasG12D介导的胰腺癌的发生和体内mPanIN的形成中。3)确定PKC的作用？在K-RasG12D介导的PDAC中。由于PDAC患者预后不佳，NCI已将胰腺癌研究确定为优先资助项目。建议的研究是高度翻译的，100%与胰腺癌相关，目的是描述对PKC？在致癌K-ras介导的胰腺化生中，mPanIN的形成和进展为PDAC。此外，我们还将表征(S)PKC？在致癌过程中起重要作用。这些研究的意义因以下事实而增强：通过治疗靶向PKC？目前存在。因此，通过这些临床前研究获得的见解可能转化为PDAC患者的新治疗策略。 公共卫生相关性：胰腺癌是一种高度致命的疾病，其特点是对传统疗法极端耐药；因此，有必要为治疗这种疾病的分子靶向疗法确定新的潜在靶点。这个项目将检验这样的假设：蛋白激酶C(PKC？)是胰腺癌的发生和发展所必需的，使用这种疾病的良好特征的小鼠模型。FDA批准的aPKC信号分子靶向抑制剂可用于癌症化疗；因此，拟议的研究有可能对胰腺癌患者的临床治疗产生直接影响。

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a highly lethal disease, marked by extreme resistance to conventional therapies; thus, there is a need to identify new potential targets for molecularly-targeted therapies to treat this disease. This project will test the hypothesis that protein kinase C iota (PKC?) is required for initiation and progression of pancreatic cancer using a well-characterized mouse model of this disease. An FDA-approved molecularly- targeted inhibitor of aPKC signaling is available as a cancer chemotherapeutic; therefore, the proposed studies have the potential to have immediate impact on the clinical practice of treatment of pancreatic cancer patients.