Genetic and Signaling Pathways in Epithelial Thyroid Cancer

描述（由申请人提供）：本P01的主要目标是通过识别基因“高危”个体，允许早期诊断和预测肿瘤行为，影响癌症发展和进展的新途径，以及通过改进现有疗法或验证新的治疗靶点来改善转移性疾病患者的预后和生活。有几个因素支持将这些努力应用于甲状腺癌的重要性：(1)甲状腺癌发病率在美国所有恶性肿瘤中上升速度最快。(2)甲状腺癌早期诊断为典型的无痛病程，因此随着发病率的增加，长期存活的个体越来越多。(3)对于侵袭性更强的甲状腺癌患者，目前的治疗方案需要改进或用更有效的治疗方法替代。在P01的第一个周期中，我们的团队共同努力实现这些目标，并对分化型甲状腺癌（乳头状癌和滤泡癌）患者的潜在影响进行了关键观察。这次比赛的目标是

DESCRIPTION (provided by applicant): The primary goal of this P01 is to improve the outcomes and lives of patients with thyroid cancer by identifying genetically "at-risk" individuals allowing for early diagnosis and prediction of tumor behavior, new pathways that influence cancer development and progression, and improving outcomes of patients with metastatic disease by improving existing therapies or validating new treatment targets. Several factors support the importance of applying these efforts to thyroid cancer: (1) Thyroid cancer incidence is rising at the fastest rate of all malignancies in the United States. (2) Thyroid cancer typical takes an indolent course when patients are diagnosed early, thus with the increasing incidence there is an ever enlarging population of individuals surviving long-term. (3) For patients with more aggressive forms of thyroid cancer, current treatment options need to be improved or replaced with more effective treatments. Over the course of the first cycle of this P01 our group has together worked toward these goals and made key observations with potential to impact on patients with differentiated thyroid cancer (papillary and follicular). The goal for this competing renewal is to extend the work on the most promising findings that have greatest likelihood to be translated into practice or that represent key advances in the field with potential to alter paradigms used in research or clinical practice. Specifically, we will functionally characterize genes that predispose to PTC in families identified in the first cycle of the P01 and apply new technologies to a larger number of informative families to identify more potential genes that predispose to PTC (Project 1), extend the work using a candidate gene approach for FTC and PTC risk that has identified interactions between signaling pathways (Project 2); design approaches to enhance 1-131 therapy using novel mouse imaging techniques developed in the P01 and extend that work to identify other unknown regulators of this process (Project 3); and fully determine the role and potential therapeutic importance of p21 activated kinase (PAK), a newly identified signaling pathway downstream of BRAF, in thyroid cancer in vivo, and determine its role in resistance to RAF inhibitors (Project 4).