Studies of Benign and Malignant Thyroid Disease

良性和恶性甲状腺疾病的研究

• 批准号: 10700666
• 负责人: Joanna Klubo-Gwiezdzinska
• 金额: $ 33.07万
• 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/10700666
• 关键词: Adult; Askenazy Cells; Benign; Blood specimen; Cancer cell line; Diagnosis; Diagnostic; Epigenetic Process; Excision; Experimental Designs; Fine needle aspiration biopsy; Goals; Human; In Vitro; Incidence; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of thyroid; Methods; Modeling; Molecular; Molecular Target; Multiple Endocrine Neoplasia Type 2a; Natural History; Neoplasm Metastasis; Nodule; Operative Surgical Procedures; Outcome; PET/CT scan; Patient Participation; Patients; Prognosis; Protocols documentation; Radioactive Iodine; Radiolabeled; Rattus; Recurrent disease; Role; SSTR2 gene; Sampling; Scanning; Specimen; Study Subject; Techniques; Testing; Thyroid Diseases; Thyroid Gland; Thyroid Nodule; Tissue Sample; Tissues; Translating; Treatment Efficacy; X-Ray Computed Tomography; Xenograft procedure; analog; bench to bedside; immunohistochemical markers; in vivo; molecular marker; mouse model; novel; pancreatic cell line; patient screening; research study; somatostatin analog; somatostatin receptor 2; standard care; targeted imaging; targeted treatment; testing uptake; treatment response; tumor; uptake

Purpose: 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. Experimental design: We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUVmax) of SSTR2 analogue, 68Ga-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 in vitro 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 in vivo. Results: Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest 68Ga-DOTA-TATE uptake median SUVmax, 16.5 (7.9-29) than other types of thyroid cancers. In vivo studies demonstrated that radiolabeled DOTA-EB-TATE 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 somatostatin (SST) analogues uptake (SUVmax, 15.16 4.34), but had no effects in a model with low SST analogues uptake (SUVmax, 4.8 0.27). Conclusions: A novel SST analogue, 177Lu-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.

目的：本研究的目的是通过分析 SSTR2 表达及其表观遗传调节并测试肿瘤对不同放射性标记 SSTR2 类似物的摄取，分析生长抑素受体 2 型 (SSTR2) 作为甲状腺癌成像和治疗分子靶点的作用。 实验设计：我们通过免疫染色分析了 92 份甲状腺癌组织样本的 SSTR2 表达，并通过 PET/CT 成像对 25 名转移性甲状腺癌患者的 SSTR2 类似物 68Ga-DOTA-TATE 的标准摄取值 (SUVmax) 进行了量化。我们利用以差异 SSTR2 表达为特征的人甲状腺癌细胞系（TT、BCPAP 和 FTC133）和具有本质上高 SSTR2 表达的大鼠胰腺细胞系（AR42J）进行功能性体外研究。使用 SSTR2-high (AR42J) 和 SSTR2-low (FTC133) 异种移植小鼠模型来测试放射性标记的 SSTR2 类似物的摄取及其体内治疗效果。 结果：甲状腺癌的SSTR2表达高于正常甲状腺。 Hurthle 细胞甲状腺癌的特点是 68Ga-DOTA-TATE 摄取中位数 SUVmax 最高，比其他类型的甲状腺癌高 16.5 (7.9-29)。体内研究表明，放射性标记的 DOTA-EB-TATE 的特点是肿瘤摄取显着高于 DOTA-TATE (P < 0.001) 和 DOTA-JR11 (P < 0.001)。在以高生长抑素 (SST) 类似物摄取为特征的小鼠模型中，使用 177Lu-DOTA-EB-TATE 治疗可延长生存期并减小肿瘤大小（SUVmax，15.16 4.34），但在低 SST 类似物摄取模型（SUVmax，15.16 4.34）中没有效果。 4.8 0.27）。 结论：一种新型 SST 类似物 177Lu-DOTA-EB-TATE 有潜力从实验室转化为临床，用于对转移性病灶中 SST 类似物高摄取的患者进行靶向治疗。