Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.
Clinical Center, NIH, Bethesda, Maryland.
Clin Cancer Res. 2021 Mar 1;27(5):1399-1409. doi: 10.1158/1078-0432.CCR-20-3453. Epub 2020 Dec 22.
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 through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues.
We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUV) of SSTR2 analogue, Ga-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy .
Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest Ga-DOTA-TATE uptake [median SUV, 16.5 (7.9-29)] than other types of thyroid cancers. studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE ( < 0.001) and DOTA-JR11 ( < 0.001). Treatment with Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUV, 15.16 ± 4.34), but had no effects in a model with low SST analogues uptake (SUV, 4.8 ± 0.27).
A novel SST analogue, Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.
本研究旨在通过分析生长抑素受体 2（SSTR2）的表达及其表观遗传调控，以及检测不同放射性标记的 SSTR2 类似物在肿瘤中的摄取，分析 SSTR2 作为甲状腺癌成像和治疗的分子靶标的作用。
我们通过对 92 例甲状腺癌组织样本的免疫染色分析 SSTR2 的表达，并对 25 例转移性甲状腺癌患者进行 SSTR2 类似物 Ga-DOTA-TATE 的 PET/CT 成像，定量标准摄取值（SUV）。我们利用具有不同 SSTR2 表达特征的人甲状腺癌细胞系（TT、BCPAP 和 FTC133）和内在高 SSTR2 表达的大鼠胰腺细胞系（AR42J）进行功能研究。我们使用 SSTR2 高表达（AR42J）和 SSTR2 低表达（FTC133）的异种移植小鼠模型来测试放射性标记的 SSTR2 类似物的摄取及其治疗效果。
甲状腺癌的 SSTR2 表达高于正常甲状腺。Hurthle 细胞甲状腺癌的 Ga-DOTA-TATE 摄取最高[中位数 SUV，16.5（7.9-29）]，高于其他类型的甲状腺癌。研究表明，放射性标记的 DOTA-EB-TATE 比 DOTA-TATE（<0.001）和 DOTA-JR11（<0.001）具有更高的肿瘤摄取率。在 SST 类似物摄取较高（SUV，15.16±4.34）的小鼠模型中，Lu-DOTA-EB-TATE 治疗延长了生存时间并缩小了肿瘤体积，但在 SST 类似物摄取较低（SUV，4.8±0.27）的模型中没有效果。
新型 SST 类似物 Lu-DOTA-EB-TATE 有可能从实验室转化为临床，用于治疗 SST 类似物摄取较高的转移性病变患者的靶向治疗。
