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：本研究的目的是分析生长抑素受体2型（SSTR 2）作为甲状腺癌成像和治疗的分子靶点的作用，通过分析SSTR 2的表达及其表观遗传调节和测试不同放射性标记的SSTR 2类似物的肿瘤摄取。 实验设计：我们通过免疫染色分析了92例甲状腺癌组织样本的SSTR 2表达，并通过PET/CT成像在25例转移性甲状腺癌患者中定量了SSTR 2类似物68 Ga-DOTA-TATE的标准摄取值（SUVmax）。我们利用以差异SSTR 2表达为特征的人甲状腺癌细胞系（TT、BCPAP和FTC 133）和具有固有高SSTR 2表达的大鼠胰腺细胞系（AR 42 J）进行体外功能研究。使用SSTR 2-高（AR 42 J）和SSTR 2-低（FTC 133）异种移植小鼠模型来测试放射性标记的SSTR 2类似物的摄取及其体内治疗功效。 结果：甲状腺癌组织中SSTR 2的表达高于正常甲状腺组织。与其他类型的甲状腺癌相比，Hurthle细胞甲状腺癌的特征在于最高的68 Ga-DOTA-TATE摄取中值SUVmax，16.5（7.9-29）。体内研究表明，放射性标记的DOTA-EB-TATE的特征在于显著高于DOTA-TATE（P < 0.001）和DOTA-JR 11（P < 0.001）的肿瘤摄取。用177 Lu-DOTA-EB-TATE治疗延长了以高生长抑素（SST）类似物摄取（SUVmax，15.16 ± 4.34）为特征的小鼠模型中的存活期并减小了肿瘤大小，但在具有低SST类似物摄取（SUVmax，4.8 ± 0.27）的模型中没有效果。 结论：一种新型SST类似物，177 Lu-DOTA-EB-TATE，有可能从实验室转移到床边，用于以转移性病变中SST类似物高摄取为特征的患者的靶向治疗。