碘难治性甲状腺癌核医学分子影像学特征与TERT及BRAF突变特征关系的研究

Since its poor prognosis, radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) tends to be the difficulty and focus in the management of thyroid cancer worldwide. Early identifying and diagnosis are crucial for RAIR-DTC, and certainly could earn more time for these patients to receive other potential intervention except 131I treatment timely. Recent studies have indicated that telomerase reverse transcriptase (TERT) promoter mutation is closely associated with the invasiveness and poor prognosis of DTC, furthermore, coexisting BRAFV600E and TERTC228T mutations leads to an even worse clinicopathologic outcomes. In our previous studies, close correlations were identified between BRAF mutation and high invasiveness of DTC, and we found that distant metastatic lesions tend to be non-radioiodine avid when BRAF mutation occurs in their primary tumor. Meanwhile, abnormal lesions with both active glycometabolism and integrin ανβ3 receptor expression were identified in our patients who were suspected as RAIR-DTC with negative radioiodine scans, by using 18FDG-PET and SPECT integrin ανβ3 receptor imaging. On basis of these previous work, this project is proposed to:1) detect molecular pathological features such as TERT promoter mutation and BRAF mutation in distant metastatic DTC patients 2) establish nude mice model transplanted with different molecular characteristics RAIR-DTC cell lines 3) associate molecular pathological features with molecular imaging characteristics such as iodine metabolism, glycometabolism and integrin receptors, via both experimental and clinical studies. We aim at providing molecular-based evidence for underlying molecular mechanisms and earlier diagnosis of RAIR-DTC.

碘难治性（RAIR）分化型甲状腺癌（DTC）因其预后差而成为目前DTC诊治的难点及热点，及早识别RAIR-DTC至关重要，也将为其他早期干预治疗争取时间。最近研究显示端粒酶反转录酶（TERT）启动子突变与DTC的侵袭性、预后相关，且与BRAF同时突变时复发风险更高。本课题组以往研究显示，BRAF突变型DTC侵袭性高，且易出现摄碘差的代谢特征；而不摄碘DTC远处转移灶的18FDG-PET及SPECT整合素ανβ3受体显像常显示出葡萄糖代谢增高及整合素受体高表达特征。在此基础上，本课题拟检测RAIR-DTC的TERT启动子及BRAF突变，并采用不同分子特征RAIR-DTC细胞系制作裸鼠荷瘤模型，探讨TERT等分子特征与病灶的核医学分子影像学特征如碘、糖代谢特征及反映肿瘤新生血管生成的整合素受体表达之间的关系，为揭示RAIR-DTC的发生机制及其早期预测提供分子病理及核医学分子影像学依据。

碘难治性（radioiodine refractory, RAIR）分化型甲状腺癌（differentiated thyroid cancer, DTC）因其预后差而成为目前DTC诊治的难点及热点，及早识别RAIR-DTC至关重要，也将为其早期干预治疗争取时间。本课题在前期工作的基础上，纳入DTC患者检测其TERT启动子及BRAF突变情况，并建立相应的动物模型，探讨TERT启动子突变等分子特征与病灶的核医学分子影像学特征如碘、糖代谢特征及反映肿瘤新生血管生成的整合素受体表达之间的关系。. 主要研究结果包括：1.远处转移的分化型甲状腺癌（distatant metastatic DTC, DM-DTC）患者其原发灶TERT启动子突变与治疗后显像病灶的不摄碘特征显著相关（p＜0.001），当TERT启动子和BRAF联合突变时,DM-DTC可能更易发展为RAIR-DTC；2.18FDG与68Ga-NOTA-PRGD2 PET/CT分子影像学显像可分别从糖代谢及肿瘤新生血管生成等方面对靶向药治疗RAIR-DTC的疗效进行监测及预后判断；3.本课题组以分子病理学和分子影像学结果为依据，探索了小分子酪氨酸激酶抑制剂——阿帕替尼在中国RAIR-DTC患者中的有效性和安全性，研究发现，阿帕替尼的血清学与影像学疗效反应速且持续，不良反应可控，有可能成为控制RAIR-DTC的有效疗法；4.初步构建了局部晚期甲状腺癌的人源肿瘤小鼠模型。. 目前本课题已按计划顺利完成，主要研究结果先后在中华医学科技奖等多项科研成果评审中获得专家的肯定及奖励，并为揭示RAIR-DTC的发生机制与早期预测、制定个体化管理方案提供分子病理及核医学分子影像学依据。