Somatostatin receptors in the diagnosis and treatment of thyroid cancer

目前对转移性甲状腺细胞癌（HTC）、放射性碘无反应性甲状腺乳头状癌（PTC）和甲状腺髓样癌（MTC）的治疗并没有导致长期的完全缓解或生存率的提高。本研究的目的是分析生长抑素受体2型（SSTR2）作为甲状腺癌（TC）成像和治疗的分子靶点的作用。我们发现TC病变中SSTR2的表达高于正常甲状腺。此外，我们通过正电子发射断层扫描/计算机断层扫描（PET/CT）观察到HTC患者对SST类似物68Ga-DOTA-TATE的摄取高于PTC和MTC患者的低至中度摄取。体外功能研究使用人TC细胞系（TT， BCPAP, FTC133）和具有内在高SSTR2的大鼠胰腺细胞系（AR42J），发现丙戊酸（VAC）通过调节SSTR2启动子区域组蛋白H3和/或H4的乙酰化来增加SSTR2的表达。小鼠异种移植的体内研究表明，放射标记的DOTA-EB-TATE可以增强SST类似物的诊断和治疗效果，其特点是肿瘤摄取明显高于DOTA-TATE （p<0.001）和DOTA-JR11 （p<0.001）。在以SSTR2高表达和SST类似物高摄取（AR42J）为特征的小鼠模型中，177Lu-DOTA-EB-TATE治疗延长了生存期，缩小了肿瘤大小，但在低sstr20低SST类似物摄取（FTC133）的模型中没有效果。总之，一种新的SST类似物，177Lu-DOTA-EB-TATE，有可能从实验室转化到床边，用于转移性病变中SST类似物摄取SSTR2高表达的TC患者的靶向治疗。

The current therapy for metastatic Hrthle cell thyroid carcinoma (HTC), radioactive iodine non-responsive papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC) does not result in long-lasting complete remissions or improved survival. The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer (TC). We showed that TC lesions have higher SSTR2 expression than normal thyroid. Further, we observed higher uptake of SST analog 68Ga-DOTA-TATE by positron emission tomography/computed tomography (PET/CT) in HTC patients in comparison to low-to-moderate uptake in PTC and MTC patients. Functional in vitro studies using human TC cell lines (TT, BCPAP, FTC133), and a rat pancreatic cell line with intrinsically high SSTR2 (AR42J), revealed that valproic acid (VAC) increases SSTR2 expression by regulating the acetylation of histone H3 and/or H4 at the SSTR2 promoter region. In vivo studies using mice xenografts demonstrated that diagnostic and therapeutic efficacy of SST analogs could be enhanced by utilizing radiolabeled DOTA-EB-TATE, which is characterized by significantly higher tumor uptake than DOTA-TATE (p<0.001) and DOTA-JR11 (p<0.001). Treatment with 177Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high SSTR2 tumor expression and high SST analogs uptake (AR42J) but had no effects in a model with low SSTR2low SST analogs uptake (FTC133). Overall, a novel SST analog, 177Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of TC patients characterized by high SST analogs uptake SSTR2 expression in metastatic lesions.