CCND1基因扩增对帕博西林治疗肝细胞癌增敏作用的研究

Sorafenib is the only first-line target drug approved in advanced hepatocellular carcinoma (HCC) but it has a low response rate. It’s of significant clinical value to explore novel target therapeutical strategies and drug sensitivity biomarkers. Precision medicine, which directs the use of target agents with genomic variations has provided new research insights for drug therapy of HCC. The cyclin dependent kinase (CDK) inhibitor Palbociclib is a potential target drug for HCC. Our previous work found 10% HCCs harbored CCND1 amplification, preliminarily observed correlation between CCND1 amplification and overexpression of cyclin D1, and cyclin D1 could activate CDK to enhance the antitumor effect of Palbociclib in HCC. This study aims to further evaluate the clinical significance of CCND1 amplification and validate the correlation between CCND1 amplification and cyclin D1 overexpression in a larger HCC cohort. We would also evaluate the sensitizing effect of CCND1 amplification on Palbociclib treating HCC as well as analyze the molecular mechanism both in vitro and in vivo. Furthermore, the anti-HCC effect of Palbociclib, the sensitizing effect of CCND1 amplification and its role as drug sensitivity marker would be confirmed in our previously established patient-derived xenograft (PDX) models. This study would systematically elucidate the sensitizing effect of CCND1 amplification on Palbociclib and the underlying mechanism, and clarify the clinical value of CCND1 amplification as drug sensitivity marker of Palbociclib, which might provide novel strategy for HCC target therapy.

肝癌唯一一线靶向药物索拉非尼应答率低，探索肝癌新型靶向治疗策略及药敏标志物具有重要临床价值。以基因变异指导靶向用药的精准医学理念为肝癌药物治疗提供了新方向。细胞周期蛋白依赖性激酶（CDK）抑制剂帕博西林是肝癌潜在靶向药物，我们前期研究发现10%的肝癌存在CCND1扩增，并与细胞周期蛋白D1（cyclin D1）高表达相关，cyclin D1激活CDK可增强帕博西林抗肝癌效果。本项目将进一步扩大样本量验证肝癌CCND1扩增和cyclin D1表达相关性及其临床意义，体内外评估CCND1扩增对帕博西林治疗肝癌的增敏作用并探讨其分子机制，再利用已构建的病人来源肿瘤移植模型（PDX）验证帕博西林抗肝癌效果、CCND1扩增的增敏作用及作为药敏标志物的可行性。本项目将系统阐明CCND1扩增对帕博西林治疗肝癌的增敏作用及机制，明确CCND1扩增作为帕博西林药敏标志物的临床价值，为肝癌靶向治疗提供新策略。

肝癌唯一一线靶向药物索拉非尼应答率低，探索肝癌新型靶向治疗策略及药敏标志物具有重要临床价值。以基因变异指导靶向用药的精准医学理念为肝癌药物治疗提供了新方向。细胞周期蛋白依赖性激酶（CDK）抑制剂帕博西林是肝癌潜在靶向药物，我们前期研究发现10%的肝癌存在CCND1扩增，并与细胞周期蛋白D1（cyclin D1）高表达相关，cyclin D1激活CDK可增强帕博西林抗肝癌效果。本项目将进一步扩大样本量验证肝癌CCND1扩增和cyclin D1表达相关性及其临床意义，体内外评估CCND1扩增对帕博西林治疗肝癌的增敏作用并探讨其分子机制，再利用已构建的病人来源肿瘤移植模型（PDX）验证帕博西林抗肝癌效果、CCND1扩增的增敏作用及作为药敏标志物的可行性。本项目研究结果阐明了CCND1扩增对帕博西林治疗肝癌的增敏作用及机制，明确CCND1扩增作为帕博西林药敏标志物的临床价值，为肝癌靶向治疗提供新策略。