Somatostatin receptors in the diagnosis and treatment of thyroid cancer

我们通过分析入选甲状腺癌基因组图谱（TCGA）的507例乳头状甲状腺癌患者的RNA seq数据，记录了生长抑素受体2型（SSTR2）在甲状腺癌中的表达，发现SSTR2在肿瘤组织中的表达高于正常甲状腺组织（p=0.003）。64例甲状腺癌组织样本的免疫组化染色显示，61%的甲状腺癌样本高表达SSTR2。我们利用人乳头状和滤泡性甲状腺癌的体外模型，记录了SSTR2在检查的人甲状腺癌细胞系中的适度表达。我们已经证明SSTR2的表达受表观遗传机制控制，并且通过参与表观遗传调控的某些药物治疗可导致SSTR2在体外过表达。我们建立了转移小鼠模型，使用免疫功能低下的小鼠在尾静脉注射人甲状腺癌细胞后发生肺和肝转移。我们在该模型中通过PET/CT成像显示转移性病变中有中等水平的放射性标记SSTR2类似物摄取。这些初步数据表明：(1)SSTR2在甲状腺癌中表达；(2)参与表观遗传调节的药物可以增加SSTR2的表达；(3)基于SSTR2的成像和治疗可以在我们建立的甲状腺癌转移小鼠模型中进行测试。

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.