Role of PKC iota in metaplasia and initiation of pancreatic cancer

PKC iota 在胰腺癌化生和发生中的作用

• 批准号: 8594229
• 负责人: Nicole R Murray
• 金额: $ 31.2万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594229
• 关键词: Adenocarcinoma Cell; Cancer Patient; Cell Line; Cells; Data; Disease; Ductal; Epithelium; FDA approved; Funding; Genetic; Goals; Growth; Human; In Vitro; Lesion; MAPK3 gene; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metaplasia; Modeling; Molecular; Mus; Mutate; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Phenotype; Play; Process; Proto-Oncogenes; Resistance; Role; Signal Pathway; Signal Transduction; Staging; System; Testing; Therapeutic Intervention; Transgenic Model; Translating; Tumorigenicity; anticancer research; base; carcinogenesis; clinical practice; conventional therapy; design; in vivo; in vivo Model; inhibitor/antagonist; insight; mouse model; neoplastic; notch protein; outcome forecast; pancreatic neoplasm; preclinical study; protein kinase C iota; public health relevance; treatment strategy; tumor; tumorigenesis

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.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种侵袭性、高度致命的疾病，其特点是对传统疗法极度耐药。因此，需要更好地了解驱动 PDAC 的信号通路，并确定治疗这种疾病的分子靶向疗法的新潜在靶点。 K-ras 原癌基因在绝大多数 PDAC 中发生突变，并且对于维持许多 PDAC 细胞系的转化表型是必需的。致癌 K-ras 在 PDAC 的发生和进展中也发挥着关键作用。小鼠胰腺上皮中致癌 K-ras 的表达诱导导管化生，随后形成癌前病变，即小鼠胰腺上皮内瘤变 (mPanIN)，并能够进展为 PDAC。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，针对致癌 K-ras 的治疗努力尚未成功，导致人们大力努力确定更适合治疗干预的 K-ras 关键下游效应子。我们发现蛋白激酶 C iota (PKC?)（其他系统中已知的致癌 K-ras 下游效应子）在人类胰腺肿瘤中高度过度表达，并且肿瘤 PKC?? 的高表达与患者生存率低相关。此外，我们发现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 PKC?-Rac1-MEK/ERK1/2 信号轴来驱动 PDAC 细胞的转化生长。根据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促癌信号通路来驱动胰腺癌发生。设计了三个相互关联的具体目标来检验这些假设。 1) 剖析 K-ras 介导的化生所需的 PKC? 调节信号机制。 2）评估PKC的作用？ K-rasG12D 介导的体内胰腺癌发生和 mPanIN 形成的启动。 3）确定PKC的作用？在 K-rasG12D 介导的 PDAC 中。由于 PDAC 患者预后不良，NCI 将胰腺癌研究确定为资助重点。拟议的研究具有高度转化性，并且与胰腺癌 100% 相关，其目标是描述 PKC 的要求？在致癌 K-ras 介导的胰腺化生、mPanIN 形成和进展为 PDAC 中。此外，我们将通过哪个 PKC 来表征分子机制？有助于致癌过程。治疗靶向 PKC 的能力这一事实增强了这些研究的重要性？目前存在。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。