Role of atypical PKCs in Pancreatic Tumor Growth and Metastasis

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因，总体5年存活率为5%。美国癌症协会估计，2007年，美国约有37170人被诊断出患有胰腺癌，约33370人将死于这种疾病。胰腺癌预后差的原因是临床表现较晚、局部侵袭、早期转移和对化疗反应差。在90%的侵袭性胰腺导管腺癌(PDAC)中检测到致癌的K-ras突变。致癌K-ras及其下游效应通路是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？)在体外和体内的致癌K-ras信号转导中。我们的初步结果表明，胰腺癌和多个人胰腺癌细胞表达PKC？那么PKC呢？PKC的基因或药物抑制？那么PKC呢？阻断体外转化的人胰腺癌细胞生长。APKCs的基因抑制抑制了体内肿瘤细胞的增殖，阻断了Hedgehog(HH-GLI)信号通路的活性。基于这一初步数据，我们假设APKCs在体内胰腺肿瘤的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。为了检验这一假说，本文提出了三个具体目标。在目标1中，我们将在PDAC的原位模型中确定aPKC的药物抑制是否能阻止肿瘤的生长和转移，在目标2中，我们将在PDAC的原位模型中确定aPKC是否是生长和转移所必需的，在目标3中，我们将评估在PDAC的原位模型中抑制aPKC信号对胰腺肿瘤致癌细胞信号的影响。这些拟议研究的完成将产生关于胰腺癌生长和转移中对aPKC的需求的重要体内数据，并将提供分子靶向的aPKC抑制物抑制胰腺癌生长和转移的能力的特征。此外，我们将开始剖析由APKCs调控的致癌信号通路，使我们能够对未来可能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，以支持全面的赠款申请，以评估APKC作为临床环境下PDAC化疗的潜在靶点。 公共卫生相关性：胰腺癌是实体肿瘤中存活率最低的，因为它的发现晚，转移早，对传统化疗耐药。该项目将在临床前模型中描述胰腺癌生长和转移中对非典型蛋白激酶Cs(APKC)的需求。这些研究的结果可能会为未来利用APKCs的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APKCs在致癌信号中的作用，着眼于合理设计治疗胰腺癌的联合治疗研究。

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.