Genetic and Signaling Pathways in Epithelial Thyroid Cancer

描述(申请人提供)：P01的主要目标是通过识别基因高危个体来改善甲状腺癌患者的预后和生活，以便对肿瘤行为进行早期诊断和预测，影响癌症发展和进展的新途径，并通过改进现有治疗方法或验证新的治疗目标来改善转移性疾病患者的预后。有几个因素支持将这些努力应用于甲状腺癌的重要性：(1)甲状腺癌发病率以美国所有恶性肿瘤中最快的速度上升。(2)甲状腺癌确诊早，病程平缓，随着发病率的增加，长期生存的个体不断扩大。(3)对于更具侵袭性的甲状腺癌患者，目前的治疗方案需要改进或用更有效的治疗方案取而代之。在P01的第一个周期中，我们团队朝着这些目标共同努力，并提出了可能对分化型甲状腺癌(乳头状癌和滤泡癌)患者产生影响的关键观察结果。这场比赛的目标是 更新是延长最有希望的发现的工作，这些发现最有可能转化为实践，或代表该领域的关键进展，有可能改变研究或临床实践中使用的范式。具体地说，我们将在P01的第一个周期中确定家系中易患PTC的基因的功能特征，并将新技术应用于更多信息丰富的家系，以确定更多易患PTC的潜在基因(项目1)，使用已确定信号通路之间相互作用的FTC和PTC风险候选基因方法来扩展工作(项目2)；使用在P01中开发的新的老鼠成像技术设计方法以加强1-131治疗，并将这项工作扩展到确定这一过程的其他未知调节因素(项目3)；并充分确定新发现的BRAF下游信号通路p21激活的激酶(PAK)在体内甲状腺癌中的作用和潜在的治疗重要性，并确定其在抵抗RAF抑制剂中的作用(项目4)。

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).