Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer

甲状腺癌 PI3K/Akt 通路中的分子事件

• 批准号: 8264949
• 负责人: MICHAEL Mingzhao XING
• 金额: $ 33.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264949
• 关键词: Ablation; BRAF gene; Behavior; Biological Assay; Cancer cell line; Capillary Electrophoresis; Cells; Characteristics; Clinical; Coupled; Coupling; DNA; DNA Methylation; DNA Sequence; Data; Databases; Development; Diagnostic; Endocrine; Endocrine system; Epidermal Growth Factor Receptor; Epigenetic Process; Equipment; Event; Follicular thyroid carcinoma; Gene Expression; Gene Mutation; Gene Silencing; Genes; Genetic; Goals; Health; Histologic; Human; In Situ Hybridization; Incidence; Iodides; Laboratories; Lead; Link; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of thyroid; Methylation; Microarray Analysis; Mitogen-Activated Protein Kinases; Molecular; Mutation; Mutation Analysis; Oncogenes; Oncogenic; Outcome; PDGFRB gene; PIK3CA gene; PTEN gene; Papillary thyroid carcinoma; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Play; Prevalence; Process; Prognostic Marker; Protocols documentation; Publishing; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Signal Pathway; Signal Transduction; Source; Statistical Methods; System; Testing; Therapeutic; Thyroid Gland; Time; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Vascular Endothelial Growth Factor Receptor-1; anaplastic thyroid cancer; base; cancer cell; clinically relevant; driving force; experience; follicular epithelial cell; improved; inhibitor/antagonist; insight; molecular marker; novel; novel diagnostics; novel strategies; novel therapeutics; prognostic; promoter; small hairpin RNA; therapeutic target; thyroid neoplasm; tumor

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.

描述（由申请人提供）：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。需要为该癌症制定更有效的管理策略，并且需要更好地了解其分子机制。 PI3K/AKT途径最近已成为甲状腺癌分子扰动的主要来源。特别是，在甲状腺癌的发病机理中，人们可以想象，在很大程度上尚未探索的途径及其关系内或与其关系相关的遗传和表观遗传改变。因此，我们建议追求四个特定的目标，以测试我们的中心假设，即改变重要基因的甲基化（例如肿瘤抑制基因，甲状腺碘化物处理基因和癌基因的甲基化偶联）与PI3K/AKT途径的基因疗法是一种基本的机械性，是PI3K/AKT途径驱动的。在特定目标1中，我们将扩展我们最近对几种关键遗传改变的发现，这些变化最有效地激活了甲状腺甲状腺癌中的PI3K/AKT途径，以探索它们，以在大量的卵泡和乳头状甲状腺癌中建立PI3K/AKT途径的一般作用，以建立thyroid cancer的一般作用。 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通过CPG甲基化微阵列分析揭示的潜在新型高甲基化肿瘤抑制基因和降压癌基因与PI3K/AKT途径结合。我们进一步假设，如果遗传和表观遗传学改变或与与甲状腺癌发病机理相关的PI3K/AKT途径很重要，则它们可能与甲状腺癌的临床病理学较差有关。这将在特定的目标3中进行测试，通过检查这些遗传和表观遗传学改变与甲状腺癌的临床病理结局的相关性，该策略可以揭示诊断和预后的分子标记。我们最终假设甲基化改变，因此，由于异常PI3K/AKT途径信号传导的结果，基因的表达可能是可以通过抑制这种途径来逆转的，该途径可能具有重要的治疗潜力。这将在特定的目标4中通过功能处理PI3K/AKT信号传导，然后检查甲状腺癌细胞系中所选功能重要基因的甲基化和表达的变化。这是一个新的建议，该建议首次研究PI3K/AKT途径中的遗传和表观遗传分子事件及其作为甲状腺癌发病机理中基本分子机制的关系。提出的策略将专注于选定的遗传和表观遗传变化以及经验丰富的PI实验室，该实验室配备了该项目的最先进的专业知识和设备，可以成功完成拟议的研究，这将产生对甲状腺癌病原体的分子机制的关键见解，并在甲状腺癌病原体和未发现的诊断和预测分析中提高诊断和预测分数，以培养型和预后的分子。 癌症。公共卫生相关性：甲状腺癌是内分泌系统中最常见的恶性肿瘤，在美国发病率迅速上升。在甲状腺癌的管理中遇到了几个主要的临床障碍，要求更有效的策略克服，可以最好地基于对这种癌症发病机理的分子机制的理解。提出了这项新型项目旨在探索PI3K/AKT途径中的遗传和表观遗传改变，并有望对甲状腺癌发病机理的分子机制产生重要的见解，并发现新颖的分子标记和治疗靶标，以改善患者患者的管理。