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: 6289833
• 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/6289833
• 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. The latter group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs, which have accelerated patterns of growth and/or fail to trap iodine efficiently. 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 human TCAs for in vitro studies. The relationship between the level of expression of markers of differentiation as well as mutations in growth-relevant genes, and the clinical behavior of TCA will help define the pathways responsible for thyrocyte growth and differentiation. These data will guide the development of novel clinical therapy trials to evaluate strategies of attacking aggressive TCAs by reverting them to a more benign differentiated phenotype by using differentiating agents. - thyroid, cancer, poorly-differentiated, radioiodine, dosimetry, therapy, oncogenes, tumor-suppressor genes, differentiation, apoptosis, PCR - Human Subjects

非甲状腺髓样癌（TCA）是最常见的内分泌恶性肿瘤，占内分泌癌死亡人数的大多数。尽管大多数TCA通过手术和放射性碘（I-131）消融治疗成功治疗，但多年来与这种疾病相关的死亡率保持稳定，因为这些治疗对临床侵袭性肿瘤无效。后一组由分化差和间变性的TCA组成，但也包括分化良好的TCA的某些亚组，其具有加速的生长模式和/或不能有效地捕获碘。恶性甲状腺细胞碘捕获能力的丧失可能与伴随去分化的其他细胞和分子事件相关，我们的目标是研究伴随临床侵袭性TCA自然史的分子事件以及各种分子标志物对标准治疗干预的反应。术前诊断方法包括抽吸细胞学检查、超声检查、用I-131和/或其他放射性核素进行甲状腺扫描以及用L-甲状腺素进行抑制治疗。具体问题包括：（i）优化TCA和血清甲状腺球蛋白测量中的诊断扫描方法，以诊断肿瘤复发，（ii）完善已经建立的I-131治疗给药方法，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），（iv）分析涉及TCA生长，凋亡，和有丝分裂周期调控，如促甲状腺激素受体，ras，p53，Fas/Fas配体，和ret/PTC在原发性和转移性甲状腺肿瘤，和（v）建立永生化细胞系从人的TCAs在体外研究。分化标志物的表达水平以及生长相关基因的突变与TCA的临床行为之间的关系将有助于确定负责甲状腺细胞生长和分化的途径。这些数据将指导开发新的临床治疗试验，以评估通过使用分化剂将侵袭性TCA恢复为更良性的分化表型来攻击侵袭性TCA的策略。- 甲状腺，癌症，低分化，放射性碘，剂量测定，治疗，癌基因，肿瘤抑制基因，分化，细胞凋亡，PCR -人类受试者