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: 6432169
• 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/6432169
• 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 (Tg) 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 further define the pathways responsible for thyrocyte growth and differentiation. Over the last year, we have studied the level of expression of sodium-iodide symporter (NIS) in renal metastases from thyroid primaries in patients with papillary TCA-Follicular Variant and correlated them with in vivo I-131 uptake. Further, we have reviewed 31 years of NIH (single institution) experience in 20 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define their role in the multimodality management of patients with "clinically aggressive" TCA. Additionally, in collaboration with our NCI colleagues, we have investigated the effects of a novel pro-differentiating agent, depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in poorly-differentiated TCA cell lines in vitro. Our preliminary data were encouraging for the role of this agent, as well as other similar agents, clinically. In fact, we are currently developing interventional trials aiming to revert aggressive TCAs to a more differentiated phenotype, by the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus rendering them yet again manageable by 131-I.

非髓样甲状腺癌(TCA)是最常见的内分泌恶性肿瘤，占内分泌癌死亡的大部分。虽然大多数TCA通过手术和放射性碘(I-131)消融治疗获得了成功，但多年来与这种疾病相关的死亡率一直保持稳定，因为这些治疗方法对临床侵袭性肿瘤无效。后一类包括分化较差和间变性的三氯乙酸，但也包括某些分化较好的三氯乙酸亚群，它们加速了生长模式和/或未能有效捕获碘。恶性甲状腺细胞对碘的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有关。我们的目标是研究伴随临床侵袭性TCA自然病程的分子事件，以及各种分子标志物对标准治疗干预的反应(S)。术前诊断方法包括抽吸细胞学、B超、I-131和/或其他放射性核素甲状腺扫描及L-甲状腺素抑制治疗。具体问题包括：(I)优化TCA的诊断扫描方法和血清甲状腺球蛋白(TG)测量以诊断肿瘤复发，(Ii)改进已建立的I-131治疗方法，以提高风险/收益比，(Iii)基于聚合酶链式反应(PCR)检测和量化外周血甲状腺细胞中甲状腺特异的mRNAs(例如，甲状腺球蛋白mRNAs和其他标记物的mRNAs)，(Iv)分析与Tca生长、凋亡和有丝分裂周期调节有关的基因突变，如促甲状腺激素受体、ras、p53、Fas/Fas配体，和ret/PTC在甲状腺原发肿瘤和转移性肿瘤中的作用，以及(V)建立用于体外研究的人甲状腺癌永生化细胞系。分化标志物的表达水平以及生长相关基因突变与甲状腺癌临床行为之间的关系将有助于进一步明确甲状腺细胞生长和分化的途径。在过去的一年里，我们研究了乳头状TCA-滤泡型变异型患者的甲状腺原发肾转移瘤中钠碘转运体(NIS)的表达水平，并将其与体内I-131摄取进行了相关性研究。此外，我们回顾了NIH(单一机构)31年的经验，这些患者接受了远端和局部区域转移的广泛二次手术切除，试图更好地确定它们在临床上具有侵袭性的TCA患者的多模式治疗中的作用。此外，我们与NCI的同事合作，研究了一种新型的促分化药物--去脂肽在体外诱导低分化TCA细胞系分化(即TG和NIS mRNAs的表达)和杀瘤活性中的作用。我们的初步数据对于该制剂以及其他类似制剂在临床上的作用是令人鼓舞的。事实上，我们目前正在进行介入性试验，旨在通过诱导/重新出现以前不存在的或肿瘤目前不足的碘蓄积增加，使侵袭性TCA恢复到更具差异性的表型，从而使它们再次可以通过131-I治疗。