Genetic and Signaling Pathways in Epithelial Thyroid Cancer

甲状腺癌的发病率在美国所有恶性肿瘤中以第二快的速度上升，并且每年具有增加的肿瘤特异性死亡率，使其成为重要的公共卫生问题。发病率和死亡率上升的原因尚不清楚。P01申请的目标是解决与甲状腺癌易感性、肿瘤发生和进展相关的关键问题，以提高早期诊断和有效治疗进展性疾病的潜力。根据我们小组的大量初步数据，我们建议：（1）检查和鉴定乳头状甲状腺癌的易感基因，（2）使用新的动物模型确定导致疾病的遗传形式--考登综合征--中的滤泡性甲状腺癌发展的关键变化，并将其转化为增强这种形式的甲状腺癌的术前诊断的方案，（3）使用第二种新的动物模型系统，评价和鉴定由RET/PTC 1癌基因诱导的甲状腺癌诱导和去分化的关键机制，RET/PTC 1癌基因是乳头状甲状腺癌中最常见的遗传异常之一，和（4）确定涉及滤泡状和乳头状甲状腺癌的肿瘤侵袭和运动的关键途径，重点是本P01中开发的模型，然后在体外和体内测试针对阻断这些途径的新试剂。在过去的六年里，各个项目的PI和核心的领导者创造了一个环境，成功地执行了甲状腺癌独特的整合P01。这包括一个庞大的数据库，与病理学的整合，以及成功的合作遗传学，实验室，药物开发和临床研究的记录，大约30篇合著的出版物证明了这一点。因此，该P01代表了针对甲状腺癌患者诊断和管理所面临的关键临床问题的一体化床旁到台架到床旁方法。

The incidence of thyroid cancer is rising at the second fastest rate of all malignancies in the United States and has an increasing tumor-specific mortality annually, making it an important public health problem. The reasons for this increasing incidence and rising death rate are uncertain. The goal of the P01 application is to address the key issues relating to thyroid cancer predisposition, tumorigenesis, and progression in order to enhance the potential for both early diagnosis and the effective treatment of progressive disease. Based on extensive preliminary data from our group, we propose to: (1) examine and identify predisposing genes for papillary thyroid cancer, (2) determine the critical changes responsible for the development of follicular thyroid cancer in an inherited form of the disease, Cowden syndrome, using a novel animal model, and translate this into a scheme to enhance preoperative diagnosis of this form of thyroid cancer, (3) evaluate and identify the key mechanisms of thyroid cancer induction and dedifferentiation induced by the RET/PTC 1 oncogene, one of the most common genetic abnormalities in papillary thyroid cancer, using a second novel animal model system, and (4) determine key pathways involved in tumor invasion and motility for both follicular and papillary thyroid cancers focusing on the models developed in this P01, and then test novel agents directed at blocking these pathway in vitro and in vivo. Over the past six years, the PI's of the individual projects, and the leaders of the cores have created an environment to successfully perform this integrated P01 that is unique for thyroid cancer. This includes a substantial database, integration with pathology, and a record of successful collaborative genetics, laboratory, drug development, and clinical research as evidenced by approximately thirty co-authored publications. Thus, this P01 represents an integrated Bedside-to-Bench-to-Bedside approach targeting the key clinical issues confronting the diagnosis and management of patients with thyroid cancer.