Clinically Aggressive Thyroid Cancer: Molecular Basis and Treatment Outcome

临床侵袭性甲状腺癌：分子基础和治疗结果

• 批准号: 6105907
• 负责人: NICHOLAS J SARLIS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6105907
• 关键词: adolescence (12-20); apoptosis; biomarker; cell differentiation; child (0-11); clinical research; gene mutation; human subject; human therapy evaluation; iodine; neoplasm /cancer genetics; neoplasm /cancer radionuclide diagnosis; neoplasm /cancer radionuclide therapy; neoplasm /cancer relapse /recurrence; neoplasm /cancer surgery; neoplastic growth; oncogenes; pediatric neoplasm /cancer; polymerase chain reaction; radiation dosage; radionuclide imaging /scanning; radionuclides; thyroid neoplasm; thyrotropin; tumor suppressor genes

Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) ablative therapy, the mortality associated with this disease has remained stable over the years because these therapies are not effective for clinically aggressive tumors, which have accelerated patterns of growth and/or fail to trap iodine efficiently. This group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs. The loss of iodine trapping ability by the malignant thyrocyte may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCA and the response of various molecular markers to standard therapeutic intervention(s). Preoperative diagnostic methods include aspiration cytology, ultrasonography, thyroid scanning with I-131 and/or other radionuclides, and suppression therapy with L- thyroxine. Specific issues include: (i) optimization of methods of diagnostic scanning in TCA and serum thyroglobulin measurement to diagnose tumor recurrence, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio, (iii) PCR-based detection and quantification of thyroid-specific mRNAs (e.g. thyroglobulin mRNA and mRNAs for other markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor, ras, p53, Fas/Fas ligand, and ret/PTC in primary and metastatic thyroid tumors, and (v) establishment of immortalized cell lines from TCAs for in vitro studies. The relationship between the existence or absence of markers of differentiation and mutations in growth-relevant genes, and the clinical behavior of TCA will help define the pathways responsible for thyrocyte growth and differentiation, and guide the development of new therapeutic strategies to attack clinically aggressive TCAs by reverting them to a more benign differentiated phenotype.

非髓样甲状腺癌（TCA）是最常见的甲状腺癌 常见的内分泌恶性肿瘤，造成大多数死亡 由于内分泌癌症。尽管大多数 TCA 通过手术和放射性碘 (I-131) 成功治疗 消融治疗，与这种疾病相关的死亡率 多年来保持稳定，因为这些疗法并不 对临床侵袭性肿瘤有效，加速了 生长模式和/或无法有效捕获碘。本组 由低分化和间变的 TCA 组成，但也 包括分化良好的 TCA 的某些亚组。的损失 恶性甲状腺细胞的碘捕获能力可能相关 与伴随的其他细胞和分子事件 去分化。 我们的目标是研究分子事件 伴随临床侵袭性 TCA 的自然史和 各种分子标记对标准治疗的反应 干预。术前诊断方法包括抽吸 细胞学、超声检查、I-131 甲状腺扫描和/或 其他放射性核素，以及 L-甲状腺素抑制治疗。 具体问题包括： (i) 诊断方法的优化 TCA 扫描和血清甲状腺球蛋白测量以诊断 肿瘤复发，（ii）完善已经建立的方法 进行 I-131 治疗以提高风险/效益比，(iii) 基于 PCR 的甲状腺特异性 mRNA 检测和定量 （例如甲状腺球蛋白 mRNA 和其他标记物的 mRNA） 外周血中循环的甲状腺细胞，（iv）突变分析 参与 TCA 生长、细胞凋亡和有丝分裂周期的基因 调节，如促甲状腺素受体、ras、p53、Fas/Fas 原发性和转移性甲状腺肿瘤中的配体和 ret/PTC，以及 (v) 从 TCA 建立体外永生化细胞系 研究。存在或不存在之间的关系 生长相关基因的分化和突变标记， TCA 的临床行为将有助于定义途径 负责甲状腺细胞的生长和分化，并指导 开发新的临床治疗策略 通过将其恢复为更良性的分化来抑制积极的 TCA 表型。