Role of MUC1 in Pancreatic Cancer

描述（由申请人提供）：本研究的目的是了解MUC 1糖蛋白在胰腺浸润性导管腺癌（PDA）从浸润前肿瘤（PanIN）发展和进展为浸润性腺癌中的致癌作用，并评价MUC 1靶向治疗干预治疗和/或预防这种毁灭性疾病的疗效。MUC 1（CD 227）是一种膜系粘蛋白糖蛋白，在>60%的人胰腺导管腺癌中过度表达和异常糖基化。已知肿瘤相关MUC 1与癌细胞的转移表型相关。MUC 1最近被鉴定为潜在的癌基因，并且已经成为包括PDA在内的多种癌症的治疗干预的活性靶点。MUC 1在PDA中的过度表达早已为人们所知，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MUC 1的作用。我们的假设是MUC 1在胰腺癌的发展中起着重要的致癌作用，并作为治疗干预的靶点。我们的具体目的是1）确定MUC 1在人胰腺癌细胞系中的功能作用; 2）确定对Mud缺陷型PDA小鼠中PanIN和PDA发育的影响;和3）评估对表达人MUC 1的PDA小鼠中PanIN和PDA发育的影响。这些小鼠模型提供了一个独特的机会，不仅可以了解MUC 1在胰腺癌发展过程中的作用，而且还为我们提供了在表达人MUC 1作为自身抗原的PDA小鼠中评估MUC 1靶向免疫治疗的能力。在第三个目标中，我们还提出确定新的策略来减少肿瘤微环境中肿瘤诱导的免疫抑制，以提高靶向免疫治疗的疗效。这个项目与胰腺癌非常相关。这些临床前研究将为设计更有效和新颖的治疗方法以对抗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.