Genetic and Signaling Pathways in Epithelial Thyroid Cancer

上皮性甲状腺癌的遗传和信号通路

基本信息

批准号：
8657014
负责人：
Matthew D Ringel
金额：
$ 217.65万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657014
关键词：
12q14 4q32 8q24 Address Area BRAF gene Behavior Biological Assay Cancer Family Cancer Model Candidate Disease Gene Cells Clinical Clinical Trials Data Development Diagnosis Disease Disease Progression Early Diagnosis Enhancers Epithelial Event Family Follicular thyroid carcinoma Genes Genetic Genetic Models Genomics Goals Imaging Techniques In Vitro Incidence Individual Indolent Iodine MEKs Malignant Neoplasms Malignant neoplasm of thyroid Mediating Methods Mitochondria Modeling Molecular Genetics Molecular Target Mus Neoplasm Metastasis Neoplasms Oncogenes Outcome PTEN gene Papillary thyroid carcinoma Pathogenesis Pathway interactions Patients Play Population Predisposition Primary Neoplasm Process Regulation Research Resistance Risk Risk Assessment Role Signal Pathway Signal Transduction Susceptibility Gene Testing Therapeutic Thyroid Gland Tissues Toxic effect Translating United States Variant Woman Work base cancer cell cancer genetics cancer risk cell motility clinical care clinical practice design effective therapy genetic linkage analysis genetic variant improved in vivo inhibitor/antagonist kinase inhibitor kindred member men model design mouse model new technology new therapeutic target novel p21 activated kinase positional cloning small molecule tumor tumor progression tumorigenesis uptake

项目摘要

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 typicall 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).

描述（由申请人提供）：该P01的主要目标是通过识别遗传“处于危险”个体来改善甲状腺癌患者的结局和生活允许早期诊断和预测肿瘤行为，影响癌症发育和进展的新途径，并通过改善现有疗法或验证新的治疗靶标的转移性疾病患者的结局。几个因素支持将这些努力应用于甲状腺癌的重要性：（1）甲状腺癌的发生率正在以美国所有恶性肿瘤中最快的速度上升。（2）甲状腺癌的典型疾病会在早期诊断出患者时采取懒惰的病程，因此随着发病率的增加，长期存活的个体人数不断扩大。（3）对于具有更具侵略性的甲状腺癌的患者，需要改善或更有效的治疗方法来改善或取代。在这个P01的第一个周期的过程中，我们的小组共同朝着这些目标努力，并进行了关键观察，并有可能影响分化甲状腺癌（乳头状和卵泡）的患者。这个竞争的目标更新是将工作扩展到最有前途的发现，这些发现可能最大程度地翻译成实践，或者代表该领域的主要进步，并有可能改变研究或临床实践中使用的范式。具体而言，我们将在功能上表征在P01第一个周期中鉴定出的家族中PTC的基因，并将新技术应用于更多的信息家庭，以识别易于PTC（项目1）的更多潜在基因（Project 1），扩展了使用FTC和PTC风险的候选基因方法来扩展工作的工作，这些基因在FTC和PTC风险中识别出信号途径（Project 2）（Project 2）; Project 2）;使用P01中开发的新型小鼠成像技术增强1-131治疗的设计方法，并扩展了该过程的其他未知调节剂（项目3）；并充分确定p21活化激酶（PAK）的作用和潜在治疗意义，这是BRAF下游的新鉴定的信号通路，体内甲状腺癌，并确定其在对RAF抑制剂抗性中的作用（项目4）。