Clinically Aggressive Thyroid Cancer: Molecular Basis An

临床侵袭性甲状腺癌：分子基础

• 批准号: 6546665
• 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/6546665
• 关键词: apoptosis; biomarker; cell differentiation; clinical research; fluorine; gene mutation; human subject; human therapy evaluation; iodine; messenger RNA; neoplasm /cancer genetics; neoplasm /cancer radionuclide diagnosis; neoplasm /cancer radionuclide therapy; neoplasm /cancer relapse /recurrence; neoplasm /cancer surgery; oncogenes; outcomes research; polymerase chain reaction; positron emission tomography; radiation dosage; radionuclide imaging /scanning; radionuclides; thyroglobulin; thyroid neoplasm; 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) therapy (i.e. ablation of normal thyroidal postoperative "remnant" and treatment of metastases), 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 show accelerated patterns of growth and/or fail to trap iodine efficiently. The loss of iodine concentrating ability by the malignant thyrocytes 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 TCAs and the response of various molecular markers to standard therapeutic intervention(s), as well as investigate the feasibility of new therapies in pilot clinical trials through translational clinical research. Preoperative diagnostic methods include aspiration cytology (fine needle), tissue core surgical biopsy, neck ultrasonography and other conventional radiographic imaging, whole body scanning with I-131 or I-123 -as well as other radionuclides -, and suppression therapy trial with L- thyroxine. Specific aims of this study include: (i) optimization of methods of diagnostic imaging in TCA (especially using non-RAI-based radionuclides, such as 111In-octreotide and 18F-fluorodeoxyglucose positron emmission tomography) and serum thyroglobulin (Tg) measurement to diagnose residual/recurrent metastatic disease, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio (such as whole body and blood dosimetry and lesional dosimetry), (iii) PCR-based detection and quantification of thyroid-specific tumoral mRNAs (e.g. thyroglobulin mRNA and mRNAs for other tumor 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 (TSHR), ras, p53, Fas/Fas ligand, ret/PTC, p53, mib1 and PCNA in primary and metastatic thyroid tumors, and, finally, (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 expanded on our review of 3 decades of NIH (single institution) experience in 32 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define the role of aggressive metastatectomies in the multimodality management of patients with TCA. Additionally, in collaboration with our colleagues from the NCI, we are currently preparing a Phase II clinical trial investigating the effects of a novel, low-toxicity histone deacetylase inhibitor with pro-differentiating properties, i.e. depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in patients with TCA unresponsive to standard treatment methods. The desired therepeutic effect would be the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus the ability to render such tumors yet again manageable by 131-I. We are also planning to investigate the role of paclitaxel as a radiosensitizing agent in a pilot clinical trial in conjunction with either conventional radiotherapy or intensity-modulated radiotherapy (IMRT) in patients with locally advanced metastatic disease in the neck and upper mediastinum, which threatens vital neck structures and currently has no effective treatment options.

非甲状腺髓样癌（TCA）是最常见的内分泌恶性肿瘤，占内分泌癌死亡的大多数。尽管大多数tca通过手术和放射性碘（I-131）治疗（即消融正常甲状腺术后“残余”和治疗转移）成功治疗，但与该疾病相关的死亡率多年来一直保持稳定，因为这些疗法对“临床侵袭性”肿瘤无效。后一类由低分化和间变性tca组成，但也包括某些分化良好的tca亚群，它们表现出加速生长和/或不能有效捕获碘的模式。恶性甲状腺细胞碘浓缩能力的丧失可能与其他伴随去分化的细胞和分子事件有关。我们的目标是研究伴随临床侵袭性TCAs的自然史的分子事件，以及各种分子标记物对标准治疗干预的反应，并通过转化临床研究探讨新疗法在中试临床试验中的可行性。术前诊断方法包括穿刺细胞学检查（细针）、组织核心手术活检、颈部超声等常规影像学检查、I-131或I-123及其他放射性核素全身扫描、L-甲状腺素抑制治疗试验。本研究的具体目的包括：(i)优化TCA诊断成像方法（特别是使用非放射性核素，如111In-octreotide和18f -氟脱氧葡萄糖正电子发射断层扫描）和血清甲状腺球蛋白（Tg）测量来诊断残留/复发转移性疾病，（ii）改进已经建立的i -131治疗方法，以提高风险/效益比（如全身和血液剂量学和病变剂量学）；（iii）基于pcr检测和定量外周血循环甲状腺细胞中甲状腺特异性肿瘤mRNA（如甲状腺球蛋白mRNA和其他肿瘤标志物mRNA）； （iv）分析原发性和转移性甲状腺肿瘤中参与TCA生长、凋亡和有丝分裂周期调控的基因突变，如促甲状腺素受体（TSHR）、ras、p53、Fas/Fas配体、ret/PTC、p53、mib1和PCNA；(5)建立人TCAs永生化细胞系用于体外研究。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进一步确定甲状腺细胞生长和分化的途径。在过去的一年里，我们对美国国立卫生研究院（NIH） 30年的32例患者的研究进行了扩展，这些患者接受了广泛的远处和局部转移性手术切除，试图更好地定义侵袭性转移性切除术在TCA患者多模式治疗中的作用。此外，与NCI的同事合作，我们目前正在准备一项II期临床试验，研究一种具有促分化特性的新型低毒组蛋白去乙酰化酶抑制剂（即沉积肽）在诱导分化（即Tg和NIS mrna的表达）中的作用，以及对标准治疗方法无反应的TCA患者的杀肿瘤活性。期望的治疗效果是诱导/重新出现先前不存在的碘或增加肿瘤目前不足的碘积累，从而有能力使这些肿瘤再次受到131-I的控制。我们还计划在一项中试临床试验中研究紫杉醇作为放射增敏剂在颈部和上纵隔局部晚期转移性疾病患者中的作用，这些疾病威胁到重要的颈部结构，目前没有有效的治疗选择。