Genetic and Signaling Pathways in Epithelial Thyroid Cancer

描述（由申请方提供）：本P01的主要目标是通过识别遗传学上的“高危”个体，从而早期诊断和预测肿瘤行为、影响癌症发展和进展的新途径，以及通过改善现有疗法或验证新的治疗靶点来改善转移性疾病患者的结局，从而改善甲状腺癌患者的结局和生活。有几个因素支持将这些努力应用于甲状腺癌的重要性：（1）甲状腺癌的发病率在美国所有恶性肿瘤中上升最快。(2)当患者被早期诊断时，甲状腺癌典型地采取无痛过程，因此随着发病率的增加，长期存活的个体人口不断增加。(3)对于患有更具侵袭性形式的甲状腺癌的患者，需要改进目前的治疗方案或用更有效的治疗方法取代。在P01的第一个周期中，我们的团队共同努力实现这些目标，并进行了可能影响分化型甲状腺癌（乳头状和滤泡状）患者的关键观察。这次比赛的目标是 更新是为了扩大最有希望的研究结果的工作，这些研究结果最有可能转化为实践，或者代表了该领域的关键进展，有可能改变研究或临床实践中使用的范式。具体而言，我们将在P01的第一个周期中鉴定的家族中对PTC易感基因进行功能表征，并将新技术应用于大量信息丰富的家族，以鉴定更多潜在的PTC易感基因（项目1），使用候选基因方法扩展FTC和PTC风险的工作，该方法已确定信号通路之间的相互作用（项目2）;设计方法，使用P01中开发的新型小鼠成像技术增强1-131治疗，并将该工作扩展到识别该过程的其他未知调节剂（项目3）;并充分确定p21激活激酶（PAK）的作用和潜在的治疗重要性，PAK是一种新鉴定的BRAF下游信号通路，在甲状腺癌体内，并确定其在抵抗RAF抑制剂的作用（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).