Role of MUC1 in Pancreatic Cancer

MUC1 在胰腺癌中的作用

• 批准号: 7146300
• 负责人: Pinku Mukherjee
• 金额: $ 27.96万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146300
• 关键词: adenocarcinoma; human; model; neoplasm /cancer; neoplastic cell; pancreas neoplasms; role

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.

描述（由申请人提供）：拟议的研究的目的是了解MUC1糖蛋白在胰腺（PDA）浸润性导管腺癌（PDA）中的致癌作用，从肿瘤前肿瘤（PANLNS）中的肿瘤作用，以评估不稳定的腺苷层症状，以评估MUC1用于治疗和/或预防这种毁灭性疾病。 MUC1（CD227）是一种膜束缚的粘蛋白糖蛋白过表达，在> 60％的人类导管胰腺腺癌中过表达且异常的糖基化。已知肿瘤相关的MUC1与癌细胞的转移表型有关。 MUC1最近被确定为潜在的癌基因，并且已成为包括PDA在内的几种癌症治疗干预的活跃靶标。长期以来，PDA中MUC1的表达过多，但其功能很难阐明，部分原因是缺乏适当的模型。随着siRNA技术的出现以及最新的PDA小鼠模型的发展，我们可以开始完全阐明MUC1的作用。我们的假设是MUC1在胰腺癌发育中起重要的致癌功能，并作为治疗干预的靶标。我们的具体目的是1）确定MUC1在人胰腺癌细胞系中的功能作用； 2）确定对缺乏泥浆的PDA小鼠中PANLN和PDA发育的影响； 3）评估对表达人MUC1的PDA小鼠中PANLN和PDA发育的影响。这些小鼠模型提供了一个独特而独特的机会，不仅了解MUC1在胰腺癌发育中的作用，而且还为我们提供了评估MUC1靶向的免疫疗法的能力，该PDA小鼠在PDA小鼠中表达了人类MUC1为自我抗原。在第三个目标中，我们还建议确定新的策略，以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。该项目与胰腺癌非常相关。这些临床前研究将构成设计更有效和新颖的疗法以应对与PDA相关的死亡率的基础。