原发性肝癌是临床上常见的恶性肿瘤之一，严重危害人类健康。近年来研究发现端粒酶逆转录酶（TERT）基因启动子在肝癌中频繁出现2个位点的热点突变，而在正常肝组织中没有发现突变，提示TERT启动子突变能够作为潜在的治疗靶点。我们前期通过荧光素酶报告基因系统，筛选到了二苯甲酮类小分子化合物CL248能够选择性抑制TERT启动子突变型的转录活性，并且CL248对TERT启动子突变型肝癌细胞的抑制率显著高于TERT启动子野生型。本项目拟在前期工作基础上，构建TERT启动子突变型和野生型肝癌细胞，利用细胞、动物模型，并收集临床新鲜肝癌组织，建立PDX模型明确CL248选择性抑制TERT启动子突变型肝癌细胞的作用，阐明CL248作用的药物靶点及分子机制，比较CL248与现有端粒酶抑制剂对TERT启动子突变型肝癌细胞治疗效果和毒性副作用的差异 ，明确CL248作为治疗TERT启动子突变型肝癌的潜在应用价值。

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies causing global public health burden. Recent advances discovered high frequency of telomerase reverse-transcriptase (TERT) promoter somatic mutations in HCC, whereas no similar mutations were observed in normal liver tissues, suggesting that TERT promoter mutation may serve as a new therapeutic target. In our previous study, we identified a benzophenone derivative (CL248) that selectively inhibited the transcriptional activity of TERT promoter mutations by using a luciferase reporter gene strategy. Moreover, CL248 treatment significantly suppressed the survival of TERT promoter mutation HCC cells compared with TERT promoter wildtype HCC cells. In this project, we will explore the effects of CL248 on the selective inhibition of TERT promoter mutation HCC cells through cellular and animal models (including Patient-derived tumor xenograft model) in vitro and in vivo, and clarify the downstream effectors and signal networks of CL248. We will also evaluate the advantages of CL248 on the treatment of TERT promoter mutations HCC patients compared to existing telomerase inhibitors. Our study will reveal the potential of CL248 for TERT promoter mutations targeted therapy in HCC patients.