Role of MUC1 in Pancreatic Cancer

描述(申请人提供)：拟议研究的目的是了解MUC1糖蛋白在胰腺浸润性导管腺癌(PDA)从侵袭前肿瘤(Panlns)到浸润性腺癌的发生和发展中的致癌作用，并评估MUC1靶向治疗干预治疗和/或预防这一毁灭性疾病的疗效。MUC1(CD227)是一种膜性粘蛋白糖蛋白，在60%的人胰腺导管癌中过度表达并异常糖化。已知肿瘤相关的MUC1与癌细胞的转移表型有关。MUC1最近被认为是一个潜在的癌基因，并且已经成为包括PDA在内的几种癌症治疗干预的积极靶点。MUC1在PDA中的过度表达早已为人所知，但其功能一直难以阐明，部分原因是缺乏合适的模型。随着siRNA技术的出现和最近PDA小鼠模型的发展，我们可以开始充分阐明MUC1的作用。我们的假设是，MUC1在胰腺癌的发生发展中起着重要的致癌作用，并可作为治疗干预的靶点。我们的具体目标是1)确定MUC1在人胰腺癌细胞系中的功能作用；2)确定MUD缺失的PDA小鼠对Panlns和PDA发育的影响；以及3)评估对表达人MUC1的PDA小鼠Panlns和PDA发育的影响。这些小鼠模型不仅提供了一个独特的机会，不仅可以了解MUC1在胰腺癌发展中的作用，而且还使我们能够在PDA小鼠中评估将人类MUC1表达为自身抗原的MUC1靶向免疫治疗。在第三个目标中，我们还建议确定新的策略来减少肿瘤微环境中的肿瘤诱导的免疫抑制，以提高靶向免疫治疗的疗效。这个项目与胰腺癌密切相关。这些临床前研究将为设计更有效和新的治疗方法以对抗与PDA相关的死亡率奠定基础。

DESCRIPTION (provided by applicant): The objective of the proposed study is to understand the oncogenic role of MUC1 glycoprotein in the development and progression of infiltrating ductal adenocarcinoma of the pancreas (PDA) from preinvasive neoplasias (PanlNs) to invasive adenocarcinomas, and to evaluate the efficacy of MUC1-targeted therapeutic intervention for the treatment and/or prevention of this devastating disease. MUC1 (CD227) is a membrane tethered mucin glycoprotein overexpressed and aberrantly glycosylated in >60% of human ductal pancreatic adenocarcinoma. Tumor-associated MUC1 is known to be associated with the metastatic phenotype of cancer cells. MUC1 is recently identified as a potential oncogene, and has been an active target for therapeutic intervention in several cancers including PDA. Over expression of MUC1 in PDA has long been known, but its function has been difficult to elucidate, partly due to the lack of appropriate models. With the advent of siRNA technology and the recent development of a mouse model of PDA, we can begin to fully elucidate the role of MUC1. Our hypothesis is that MUC1 plays an important oncogenic function in pancreatic cancer development and serves as a target for therapeutic intervention. Our specific aims are 1) To determine the functional role of MUC1 in human pancreatic cancer cell lines; 2) To determine the effects on the development of PanlNs and PDA in Mud -deficient PDA mice; and 3) To evaluate the effects on the development of PanlNs and PDA in PDA mice expressing human MUC1. These mouse models provide an unique and distinctive opportunity to not only understand the role of MUC1 during pancreatic cancer development, but also offers us the ability to evaluate MUC1-targeted immune therapy in the PDA mice that expresses human MUC1 as a self-antigen. In the third aim we also propose to determine novel strategies to reduce tumor-induced immune-suppression within the tumor microenvironment to improve efficacy of targeted immune therapy. This project is extremely relevant to pancreatic cancer. These preclinical studies will form the basis for designing more efficacious and novel therapies to combat the mortality associated with PDA.