Somatostatin receptors in the diagnosis and treatment of thyroid cancer

我们通过分析纳入甲状腺癌基因组图谱（TCGA）的507例甲状腺乳头状癌患者的RNA测序数据，记录了甲状腺癌中生长抑素受体2型（SSTR 2）的表达，并显示肿瘤中SSTR 2的表达高于正常甲状腺组织（p=0.003）。64例甲状腺癌组织标本的免疫组化染色显示，61%的甲状腺癌标本中SSTR 2高表达。 我们已经利用了人乳头状和滤泡性甲状腺癌的体外模型，并记录了SSTR 2在检查的人甲状腺癌细胞系中的适度表达。我们已经表明，SSTR 2的表达是由表观遗传机制和治疗与某些药物参与表观遗传调控导致SSTR 2在体外过表达。我们开发了一种转移性小鼠模型，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成像证实，在转移性病变中显示了中等水平的放射性标记的SSTR 2类似物摄取。（2）参与表观遗传调节的药理学试剂可增加SSTR 2的表达（3）基于SSTR 2的成像和治疗可以在我们开发的已建立的甲状腺癌转移性小鼠模型中进行测试。 我们的初步结果将为涉及30例转移性甲状腺癌患者的2期临床试验奠定基础，这些患者的肿瘤是放射性碘难治性的，但SSTR 2类似物-avid，利用体内模型中最有效的治疗方案。

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.