Role of atypical PKCs in Pancreatic Tumor Growth and Metastasis

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（American Cancer Society）估计，2007年，美国约有37170人被诊断出患有胰腺癌，约有33370人将死于这种疾病。胰腺癌的预后较差是由于其出现较晚，局部侵袭性强，转移早，对化疗反应差。在90%的浸润性胰腺导管腺癌（PDAC）中检测到致癌性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人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 ?。基因或药物抑制PKC？和PKC吗?体外阻断人胰腺癌细胞转化生长。基因抑制aPKCs在体内阻断肿瘤细胞增殖，阻断Hedgehog （HH-GLI）信号通路活性。基于这些初步数据，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。为了验证这一假设，提出了三个具体目标。在Aim 1中，我们将确定aPKCs的药理抑制是否会阻断PDAC原位模型中的肿瘤生长和转移；在Aim 2中，我们将确定aPKCs是否需要PDAC原位模型中的生长和转移；在Aim 3中，我们将评估aPKC信号抑制对胰腺肿瘤原位PDAC模型中致癌细胞信号传导的影响。上述研究的完成将产生关于胰腺癌生长和转移需要aPKC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，我们将开始剖析由aPKCs调控的致癌信号通路，使我们能够在未来对潜在的联合治疗做出理性的决定。拟议的研究将产生重要的初步数据，以支持全面的拨款申请，以评估aPKCs作为临床环境中PDAC化疗的潜在靶点。

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.