Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer

描述(申请人提供)：甲状腺癌是最常见的内分泌恶性肿瘤，近年来发病率迅速上升。需要为这种癌症开发更有效的治疗策略，并需要更好地了解其分子机制。最近，PI3K/Akt通路已成为甲状腺癌分子错位的主要来源。特别是，遗传和表观遗传的改变或与此途径及其关系的关联，在很大程度上还没有被研究过，可以想象是甲状腺癌发病机制中的关键分子事件。因此，我们建议追求四个特定的目标来验证我们的中心假设，即重要基因(如肿瘤抑制基因、甲状腺碘处理基因和癌基因)的甲基化变化与由其基因变化驱动的PI3K/Akt通路的耦合是甲状腺癌发病的基本机制。在具体目标1中，我们将扩展我们最近在间变性甲状腺癌中最有效地激活PI3K/Akt通路的几个关键基因改变的发现，以探索它们在大量滤泡性和乳头状甲状腺癌中的作用，为PI3K/Akt通路在甲状腺癌中的普遍作用奠定遗传学基础。与我们之前发现的与MAP激酶途径相关的异常基因甲基化以及我们最近在甲状腺癌中一些基因的甲基化与PI3K/Akt途径的联系的发现类似，我们将在特定目标2中研究PI3K/Akt途径的主要基因变化与已知肿瘤抑制基因和甲状腺碘处理基因的甲基化以及CpG甲基化微阵列分析揭示的潜在的与PI3K/Akt途径相偶联的新的肿瘤抑制基因和低甲基化癌基因的关系。我们进一步假设，如果PI3K/Akt通路的遗传和表观遗传学改变或与之关联在甲状腺癌的发病机制中是重要的，它们可能与甲状腺癌较差的临床病理结果有关。这将在特定的目标3中进行测试，方法是检查这些遗传和表观遗传变化与甲状腺癌临床病理结果的相关性，这是一种可以揭示诊断和预后分子标记的策略。我们最后假设，由于异常的PI3K/Akt通路信号，改变了甲基化从而改变了基因的表达，可能是通过抑制这一途径而可逆的，这一策略可能具有重要的治疗潜力。这将在特定的目标4中进行测试，方法是在功能上操纵PI3K/Akt信号，随后检测甲状腺癌细胞系中选定的功能重要基因的甲基化和表达的变化。这是一项首次研究PI3K/Akt途径中的遗传和表观遗传分子事件及其关系的新提议，它们是甲状腺癌发病机制中的一个基本分子机制。随着拟议的战略重点放在选定的遗传和表观遗传学改变上，以及PI的经验丰富的实验室为该项目配备了最先进的专业知识和设备，拟议的研究有望成功完成，这将对甲状腺癌发病的分子机制产生关键的见解，并发现新的诊断和预后分子标志物和治疗靶点，以改善目前对甲状腺癌患者的治疗。公共卫生相关性：甲状腺癌是内分泌系统最常见的恶性肿瘤，在美国发病率迅速上升。在甲状腺癌的治疗中遇到了几个主要的临床障碍，需要更有效的策略来克服，而最好的方法是基于对这种癌症发病机制的了解。这一新的项目旨在探索PI3K/Akt通路中的遗传和表观遗传学变化，有望对甲状腺癌发病的分子机制产生重要的见解，并发现新的分子标记和治疗靶点，以改善甲状腺癌患者的治疗。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy, with a rapidly rising incidence in recent years. Development of more effective management strategies for this cancer is needed and requires better understanding of its molecular mechanisms. The PI3K/Akt pathway has recently emerged as a major source of molecular derangements in thyroid cancer. In particular, genetic and epigenetic alterations within or linked to this pathway and their relationships, which have been largely unexplored, are conceivably critical molecular events in the pathogenesis of thyroid cancer. Consequently, we propose to pursue four Specific Aims to test our central hypothesis that coupling of altered methylation of important genes (e.g., tumor suppressor genes, thyroid iodide-handling genes, and oncogenes) to the PI3K/Akt pathway driven by its genetic alterations is a fundamental mechanism in thyroid cancer pathogenesis. In Specific Aim 1, we will extend our recent findings of several key genetic alterations that are most effective in activating the PI3K/Akt pathway in anaplastic thyroid cancer to explore them in a large set of follicular and papillary thyroid cancers to establish the genetic basis for a general role of the PI3K/Akt pathway in thyroid cancer. Analogous to our previous findings of aberrant gene methylation linked to the MAP kinase pathway and with our recent findings on the link of methylation of some genes to the PI3K/Akt pathway in thyroid cancer, we will investigate, in Specific Aim 2, the relationship of major genetic alterations in the PI3K/Akt pathway with methylation of known tumor suppressor and thyroid iodide-handling genes as well as potentially novel hypermethylated tumor suppressor genes and hypomethylated oncogenes coupled to the PI3K/Akt pathway that are revealed by CpG methylation microarray analysis. We further hypothesize that if the genetic and epigenetic alterations in, or linked to, the PI3K/Akt pathway are important in thyroid cancer pathogenesis, they are likely to be associated with poorer clinicopathological outcomes of thyroid cancer. This will be tested in Specific Aim 3 by examining the correlation of these genetic and epigenetic alterations with clinicopathological outcomes of thyroid cancer, a strategy that can reveal diagnostic and prognostic molecular markers. We finally hypothesize that altered methylation and, hence, expression of genes, as a consequence of aberrant PI3K/Akt pathway signaling, may be reversible by suppressing this pathway, a strategy that may have important therapeutic potential. This is to be tested in Specific Aim 4 by functionally manipulating the PI3K/Akt signaling and subsequently examining the change in methylation and expression of selected functionally important genes in thyroid cancer cell lines. This is a novel proposal that for the first time investigates both genetic and epigenetic molecular events in the PI3K/Akt pathway and their relationship as a fundamental molecular mechanism in thyroid cancer pathogenesis. With the proposed strategy to focus on selected genetic and epigenetic alterations and with the experienced laboratory of the PI that is equipped with state-of-the-art expertise and equipments for this project, successful completion of the proposed studies is expected, which should produce key insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel diagnostic and prognostic molecular markers and therapeutic targets to improve the current management of patients with thyroid cancer. PUBLIC HEALTH RELEVANCE: Thyroid cancer is the most common malignancy of the endocrine system, with a rapidly rising incidence in the United States. Several major clinical obstacles are encountered in the management of thyroid cancer, demanding more effective strategies to overcome that can be best based on the understanding of the molecular mechanisms in the pathogenesis of this cancer. This novel project is proposed to explore particularly genetic and epigenetic alterations in the PI3K/Akt pathway and is expected to produce important insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel molecular markers and therapeutic targets to improve the management of patients with thyroid cancer.