Clinically Aggressive Thyroid Cancer: Molecular Basis An

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。虽然大多数甲状腺癌通过手术和放射性碘(I-131)治疗(即切除正常的甲状腺术后残留物和治疗转移)得到了成功的治疗，但多年来与这种疾病相关的死亡率一直保持稳定，因为这些治疗对“临床侵袭性”肿瘤无效。后者包括分化较差和未分化的TCA，但也包括分化较好的TCA的某些亚组，这些亚组表现出加速生长的模式和/或未能有效捕获碘。 恶性甲状腺细胞对碘的浓缩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)，以及通过转译临床研究探索新疗法在试点临床试验中的可行性。 术前诊断方法包括抽吸细胞学(细针)、组织芯手术活检、颈部超声等常规X线检查、I-131或I-123全身扫描及其他放射性核素检查，以及L-甲状腺素抑制治疗试验。 这项研究的具体目标包括：(I)优化TCA的诊断成像方法(特别是使用非基于RAI的放射性核素，如111In-奥曲肽和18F-氟代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，以诊断残留/复发的转移性疾病；(Ii)改进已建立的I-131治疗方法，以提高风险/效益比(如全身和血液剂量学和皮损剂量学)；(Iii)基于聚合酶链式反应的甲状腺特异性肿瘤mRNAs(例如，甲状腺球蛋白mRNAs和其他肿瘤标记物的mRNAs)的检测和定量(4)分析甲状腺原发灶和转移瘤中促甲状腺激素受体(TSHR)、ras、P53、Fas/Fas配体、ret/PTC、P53、mib1和增殖细胞核抗原等与TCA生长、凋亡和有丝分裂周期调控有关的基因突变情况；(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，我们完成了一项关于FDG-PET扫描与111In标记的奥曲肽扫描与广泛的传统放射成像在广泛转移的TCA疾病检测中的有效性的比较研究；这是一项在其范围和程度上的独特研究。此外，我们与NCI的同事合作，准备了一项Ib期临床试验，研究一种新型、低毒、具有促分化特性的组蛋白脱乙酰酶抑制剂，即去脂肽，在诱导TCA分化(即TG和NIS mRNAs的表达)以及对标准治疗方法无效的TCA患者的杀瘤活性方面的效果。这项研究已经得到了NCI、CTEP和IRB的批准，应该很快就会招募患者。所期望的治疗效果将是诱导/重新出现以前不存在的或增加肿瘤目前不足的碘蓄积，从而使这种肿瘤再次能够通过131-I治疗。此外，与德克萨斯州休斯敦MD Anderson癌症中心的同事合作，我们已经开始研究紫杉醇(紫杉醇)作为放射增敏剂与常规放射治疗相结合在颈部和上纵隔局部晚期转移性疾病患者中的作用，这种转移性疾病威胁到重要的颈部结构，目前还没有有效的治疗方案。这项研究的试验阶段现已完成。此外，与NCI病理实验室的同事再次合作，我们已经能够完成对TCA外科病理标本的蛋白质组学分析的第一次研究。我们的发现有望在TCA中发现新的标志物、检测或生物学特征(如侵袭性)。最后，我们研究了细胞骨架相互作用蛋白EMS-1癌基因产物Cortactin在TCA中的表达模式，并发现这些模式之间存在有趣的差异，这取决于TCA的组织亚型。

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 completed a comparison study of the usefulness of FDG-PET scanning versus 111In-labeled octreotide scanning versus extensive conventional radiographic imaging for disease detection in widely metastatic TCA; a unique study in its scope and extent. Additionally, in collaboration with our colleagues from the NCI, we prepared a Phase Ib 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. This study has been already approved by the NCI CTEP and IRB and should be recruiting patients soon. 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. Moreover, in collaboration with colleagues at the MD Anderson Cancer Center in Houston, TX, we have begun to investigate the role of paclitaxel (taxol) as a radiosensitizing agent in conjunction with conventional radiotherapy 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. The pilot phase of this study has now been completed. Additionally, again with collaboration with our colleagues at the Laboratory of Pathology, NCI, we have been able to complete the first ever study of proteomics analysis of TCA surgical pathology specimens. Our findings will hopefully spearhead the identification of new markers the detection or biological features (such as aggressiveness) in TCA. Finally, we have investigated the expression patterns of cortactin, the product of the EMS-1 oncogene, a cytoskeletal-interactive protein, in TCA and have found interesting differences among these patterns depending on the histological subtype of TCA.