Somatostatin receptors in the diagnosis and treatment of thyroid cancer

生长抑素受体在甲状腺癌诊断和治疗中的作用

基本信息

批准号：
9553303
负责人：
Joanna Klubo-Gwiezdzinska
金额：
$ 30.44万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/9553303
关键词：
Cancer Patient Cancer cell line Case Series Data Diagnosis Diagnostic Imaging Disseminated Malignant Neoplasm Enrollment Epigenetic Process Follicular thyroid carcinoma Human Image Immunocompromised Host In Vitro Injection of therapeutic agent Malignant - descriptor Malignant neoplasm of thyroid Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Modeling Mus Neoplasm Metastasis Neuroendocrine Tumors PET/CT scan Papillary Papillary thyroid carcinoma Patients Pharmacology Phase II Clinical Trials RNA analysis Radioactive Iodine Radiolabeled Refractory Regimen SSTR2 gene Sampling Somatostatin Receptor Staining method Stains Tail Testing The Cancer Genome Atlas Therapeutic Thyroid Gland Thyroid Nodule Thyroidectomy Tissue Sample Tissues Treatment Efficacy United States National Institutes of Health Veins X-Ray Computed Tomography analog base cancer cell epigenetic regulation in vitro Model in vivo Model molecular targeted therapies mouse model overexpression radioiodine therapy somatostatin receptor 2 transcriptome sequencing tumor uptake

项目摘要

We documented somatostatin receptors type 2 (SSTR2) expression in thyroid cancer by the analysis of RNA seq data of 507 patients with papillary thyroid cancer enrolled in Thyroid Cancer Genome Atlas (TCGA) and showed higher expression of SSTR2 in tumor vs normal thyroid tissue (p=0.003). Immunohistochemical staining of 64 thyroid cancer tissue samples revealed high SSTR2 expression in 61% of thyroid cancer samples. We have utilized in vitro models of human papillary and follicular thyroid cancer and documented a moderate expression of SSTR2 in examined human thyroid cancer cell lines. We have shown that expression of SSTR2 is controlled by epigenetic mechanisms and treatment with certain pharmacological agents involved in epigenetic regulation leads to overexpression of SSTR2 in vitro. We developed a metastatic mouse model using immunocompromised mice developing lung and liver metastases after tail vein injection of human thyroid cancer cells. We showed a moderate level of radiolabeled SSTR2 analogs uptake in metastatic lesions as documented by PET/CT imaging in this model.These preliminary data indicate that (1) SSTR2 are expressed in thyroid cancer, (2) expression of SSTR2 could be increased by pharmacological agents involved in epigenetic modulation (3) SSTR2 based imaging and treatment can be tested in an established thyroid cancer metastatic mouse model that we have developed. Our preliminary results will form a basis for a phase 2 clinical trial involving 30 metastatic thyroid cancer patients, whose tumors are radioactive iodine refractory, but SSTR2 analogs-avid, utilizing the most effective therapeutic regimen from in vivo model.

我们通过分析甲状腺癌基因组图谱 (TCGA) 中 507 名乳头状甲状腺癌患者的 RNA 序列数据，记录了甲状腺癌中生长抑素受体 2 型 (SSTR2) 的表达，并显示肿瘤组织中 SSTR2 的表达高于正常甲状腺组织 (p =0.003）。对 64 份甲状腺癌组织样本的免疫组织化学染色显示，61% 的甲状腺癌样本中 SSTR2 高表达。我们利用了人乳头状和滤泡性甲状腺癌的体外模型，并记录了在检查的人甲状腺癌细胞系中 SSTR2 的中等表达。我们已经证明，SSTR2 的表达受表观遗传机制控制，并且用某些参与表观遗传调控的药物治疗会导致 SSTR2 在体外过度表达。我们利用尾静脉注射人甲状腺癌细胞后出现肺和肝转移的免疫功能低下的小鼠开发了一种转移性小鼠模型。我们在该模型中通过 PET/CT 成像记录显示，转移性病变中放射性标记的 SSTR2 类似物摄取水平中等。这些初步数据表明 (1) SSTR2 在甲状腺癌中表达，(2) SSTR2 的表达可通过药理学增加参与表观遗传调节的药物 (3) 基于 SSTR2 的成像和治疗可以在我们开发的已建立的甲状腺癌转移小鼠模型中进行测试。我们的初步结果将为一项涉及 30 名转移性甲状腺癌患者的 2 期临床试验奠定基础，这些患者的肿瘤具有放射性碘难治性，但对 SSTR2 类似物有强烈的需求，并利用体内模型中最有效的治疗方案。