成釉细胞瘤临床研究前模型构建及精准治疗研究前景  

Research prospect of preclinical model construction and precision therapy in ameloblastoma

作　　者：康馨丹 孙露露 张志愿[1] 孙树洋[1] Kang Xindan;Sun Lulu;Zhang Zhiyuan;Sun Shuyang(Department of Oral-Maxillofacial Head and Neck Oncology,Shanghai Ninth People′s Hospital,Shanghai Jiao Tong University School of Medicine&College of Stomatology,Shanghai Jiao Tong University&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Shanghai Key Laboratory of Stomatology&Shanghai Research Institute of Stomatology&Research Unit of Oral and Maxillofacial Regenerative Medicine,Chinese Academy of Medical Sciences,Shanghai 200011,China)

机构地区：[1]上海交通大学医学院附属第九人民医院口腔颌面-头颈肿瘤科、上海交通大学口腔医学院、国家口腔医学中心、国家口腔疾病临床医学研究中心、上海市口腔医学重点实验室、上海市口腔医学研究所、中国医学科学院口腔颌面再生医学创新单元,上海200011

出　　处：《中华口腔医学杂志》2023年第8期844-851,共8页Chinese Journal of Stomatology

基　　金：国家自然科学基金(82030085);国家重点研发计划(2017YFC0908500);上海市临床重点专科(shslczdzk01601);上海市重中之重研究中心(2022ZZ01017);中国医学科学院医学与健康科技创新工程项目(2019⁃I2M⁃5⁃037)。

摘　　要：成釉细胞瘤(ameloblastoma,AM)是病因不明,易复发、可恶变的良性牙源性肿瘤,刮治术后复发率高,颌骨部分切除术影响患者口腔颌面部结构功能。全基因组测序结果显示BRAF基因突变和SMO基因突变较常见,且二者发生倾向于互斥。个别病例报告表明BRAF抑制剂对携带BRAFV600E的患者有效,而开展大规模临床研究有困难,因此亟需可靠的临床研究前模型来探索AM靶向药物治疗。体外细胞模型及小鼠体内移植瘤模型是常见的临床研究前模型。二维培养良性肿瘤增殖能力有限,永生化处理后很可能影响细胞表型;此外,AM在裸鼠皮下移植瘤成功率较低,人源化小鼠异种移植瘤模型待更多探索。而目前三维类器官有希望实现AM干性上皮细胞亚群培养,进而模拟体内肿瘤、用于精准治疗药物研发。本文对AM临床研究前模型、遗传变异特征的研究进展展开综述,提出可进行药物筛选等研究的AM类器官模型构建的研究前景,从而为更多患者提供个性化治疗可能。Ameloblastoma(AM)is a benign odontogenic tumor with unknown etiology.It is prone to recurrence and has a potential for malignant transformation.Patients often show high rates of relapse after curettage,or suffer from structural and functional damage of jaw after partial resection.Whole-genome sequencing data revealed that BRAF mutations and SMO mutations were common and likely to be mutually exclusive in AM.It was also reported that BRAF inhibitors were effective in several patients carrying BRAFV600E mutation.However,reliable preclinical models are urgently needed for exploring targeted therapy as it′s so difficult to conduct large clinical trials in this tumor.Patient-derived cell models in vitro and xenograft models in vivo are frequently used preclinical models.In fact,benign tumor cells generally showed a finite proliferative capacity in two-dimensional culture,and most likely,they could exhibit altered cellular phenotype after immortalization.Moreover,this benign tumor presented low chances of subcutaneous engraftment in nude mice.Accordingly,humanized mouse xenograft model needs more exploration.Yet,it is worth mentioning that a three-dimensional organoid model presents a high potential in culturing stem-cell-like epithelial cells in AM,and it would further be used in recapitulating corresponding tumors and developing targeted medicines.In this paper,we review research progress in preclinical models and the genetic variations of AM,and raise drug screening prospect of the current organoid models,which may pave the way for the possible personalized medicine in AM.

关 键 词：成釉细胞瘤 临床研究前模型 类器官 基因突变 个性化治疗 

分 类 号：R739.8[医药卫生—肿瘤]