Role of atypical PKCs in Pancreatic Tumor Growth and Metastasis

非典型 PKC 在胰腺肿瘤生长和转移中的作用

• 批准号: 7769172
• 负责人: Nicole R Murray
• 金额: $ 7.65万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769172
• 关键词: American Cancer Society; Applications Grants; Cancer Etiology; Cell Proliferation; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Data; Diagnosis; Disease; Early Diagnosis; Erinaceidae; Eye; Future; Genetic; Growth; Human; In Vitro; Maintenance; Malignant neoplasm of pancreas; Modeling; Mutation; Neoplasm Metastasis; Oncogenic; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Play; Pre-Clinical Model; Protein Kinase; Resistance; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Survival Rate; Testing; United States; base; cancer cell; cancer therapy; chemotherapy; design; in vivo; inhibitor/antagonist; neoplastic cell; outcome forecast; pancreatic neoplasm; protein kinase C iota; protein kinase C zeta; public health relevance; response; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer deaths in the United States with an overall 5-year survival rate of <5%. The American Cancer Society estimated that, in 2007, approximately 37,170 people in the United States would be diagnosed with pancreatic cancer and about 33,370 would die of the disease. The poor prognosis of pancreatic cancer is attributable to its tendency for late presentation, aggressive local invasion, early metastases, and poor response to chemotherapy. Oncogenic K-ras mutations are detected in >90% of invasive pancreatic ductal adenocarcinoma (PDAC). Oncogenic K-ras and its downstream effector pathways are required for initiation and maintenance of PDAC. Our lab and others have identified a requisite role for atypical protein kinase Cs (aPKCs), PKC iota (PKC?) and PKC zeta (PKC?) in oncogenic K-ras signaling in vitro and in vivo. Our preliminary results demonstrate that pancreatic cancer, and multiple human pancreatic cancer cells express PKC? and PKC?. Genetic or pharmacological inhibition of PKC? and PKC? blocks transformed growth of human pancreatic cancer cells in vitro. Genetic inhibition of aPKCs blocks tumor cell proliferation in vivo, and blocks Hedgehog (HH-GLI) signaling pathway activity. Based on this preliminary data, we hypothesize that aPKCs play an essential role in pancreatic tumor growth and metastasis in vivo, and are therefore a potential target for pancreatic cancer therapy. Three specific aims are proposed to test this hypothesis. In Aim 1 we will determine whether pharmacological inhibition of aPKCs blocks tumor growth and metastasis in an orthotopic model of PDAC, in Aim 2 we will determine whether aPKCs are required for growth and metastasis in an orthotopic model of PDAC and in Aim 3 we will evaluate the effect of inhibition of aPKC signaling on oncogenic cellular signaling in pancreatic tumors in an orthotopic model of PDAC. Completion of the proposed studies will generate important in vivo data regarding the requirement for aPKCs in pancreatic cancer growth and metastasis, and will provide a characterization of the ability of a molecularly-targeted aPKC inhibitor to inhibit pancreatic tumor growth and metastasis. In addition, we will begin to dissect the oncogenic signaling pathways regulated by aPKCs, allowing us to make rational decisions about potential combination therapy in the future. The proposed studies will generate significant preliminary data to support a comprehensive grant application to evaluate aPKCs as a potential target for PDAC chemotherapy in a clinical setting. PUBLIC HEALTH RELEVANCE: Pancreatic cancer has the worst survival rate of any solid tumor due to its late detection, early metastasis and resistance to conventional chemotherapy. This project will characterize the requirement for atypical protein kinase Cs (aPKC) in pancreatic cancer growth and metastasis in a pre-clinical model. The results of these studies will likely provide support for future clinical trials utilizing a molecularly targeted inhibitor of aPKCs to treat pancreatic cancer. We will also evaluate the role of aPKCs in oncogenic signaling with an eye toward rational design of combination therapy studies for treatment of pancreatic cancer.

描述（由申请人提供）：胰腺癌是美国第四大癌症死亡原因，总体 5 年生存率 <5%。美国癌症协会估计，2007年，美国大约有37,170人被诊断出患有胰腺癌，大约有33,370人死于该病。胰腺癌的预后不良是由于其发病晚、局部侵袭性强、转移早、化疗反应差等原因。在 >90% 的侵袭性胰腺导管腺癌 (PDAC) 中检测到致癌 K-ras 突变。致癌 K-ras 及其下游效应途径是 PDAC 启动和维持所必需的。我们的实验室和其他实验室已经确定了非典型蛋白激酶 Cs (aPKCs)、PKC iota (PKC?) 和 PKC zeta (PKC?) 在体外和体内致癌 K-ras 信号传导中的必要作用。我们的初步结果表明，胰腺癌和多种人类胰腺癌细胞表达 PKC？和PKC？ PKC 的遗传或药理学抑制？和PKC？在体外阻断人胰腺癌细胞的转化生长。 aPKC 的基因抑制可阻断体内肿瘤细胞增殖，并阻断 Hedgehog (HH-GLI) 信号通路活性。基于这些初步数据，我们假设 aPKC 在体内胰腺肿瘤生长和转移中发挥重要作用，因此是胰腺癌治疗的潜在靶点。提出了三个具体目标来检验这一假设。在目标 1 中，我们将确定 aPKC 的药理学抑制是否会阻止 PDAC 原位模型中的肿瘤生长和转移，在目标 2 中，我们将确定 PDAC 原位模型中的生长和转移是否需要 aPKC，在目标 3 中，我们将评估原位模型中抑制 aPKC 信号对胰腺肿瘤中致癌细胞信号的影响 的 PDAC。拟议研究的完成将产生有关胰腺癌生长和转移中 aPKC 需求的重要体内数据，并将提供分子靶向 aPKC 抑制剂抑制胰腺肿瘤生长和转移能力的表征。此外，我们将开始剖析aPKCs调节的致癌信号通路，使我们能够对未来潜在的联合治疗做出合理的决定。拟议的研究将产生重要的初步数据，以支持综合拨款申请，以评估 aPKC 作为临床环境中 PDAC 化疗的潜在靶点。 公共健康相关性：由于胰腺癌发现较晚、转移较早且对传统化疗产生耐药性，因此它的生存率是所有实体瘤中最低的。该项目将在临床前模型中描述胰腺癌生长和转移对非典型蛋白激酶 Cs (aPKC) 的需求。这些研究的结果可能会为未来利用 aPKC 分子靶向抑制剂治疗胰腺癌的临床试验提供支持。我们还将评估 aPKC 在致癌信号传导中的作用，着眼于合理设计治疗胰腺癌的联合治疗研究。