基于深度测序的基因组变异指导肝癌靶向治疗的转化研究

Currently, sorafenib is the only target drug approved by FDA in hepatocellular carcinoma (HCC) but it has a poor overall effect and has no predictive biomarker of drug sensitivity. Precision medicine, which directs the use of target agents with genomic variations unrevealed by targeted deep sequencing, could make the off-label use of target agents possible and improve the effect of HCC target therapy. Previously, we have established patient derived xenograft (PDX) for anti-cancer drug screen and found that HCC had variations indicative of multiple target agents and proved the liquid biopsy value of circulating cell-free DNA (cfDNA). This study aims to construct target deep sequencing strategy specific for HCC in order to efficiently identify genomic variations for the guidance of sorafenib/off-label use of other agents in PDX, compare the treatment effects of standard therapy of sorafenib and precision therapy of off-label agents, and search for biomarkers predicting the use of sorafenib by dynamic surveillance of cfDNA. Conclusively, this study would systematically explore the translational value of directing target therapy of HCC by genomic profiling, provide initial evidence for future umbrella trials in HCC, and establish the basis of improving overall survival of HCC patients.

目前索拉非尼是FDA认证的治疗晚期肝癌的唯一靶向药物，但总体疗效较差，且无有效药敏标志物。通过深度测序发现基因组变异来指导靶向治疗的精准医学模式能够使靶向药物超说明书使用成为可能，这将有助于改善肝癌靶向治疗的疗效。前期研究建立了病人来源肿瘤异种移植模型（PDX）用于抗肿瘤药物筛选；通过深度测序发现肝癌具有多种靶向药物相关突变，并证实循环游离DNA（cfDNA）的“液体活检”价值。本项目拟构建肝癌特异性靶向深度测序方案，高效挖掘肝癌基因组变异，并以此在PDX模型中指导索拉非尼和其它靶向药物的超说明书使用，进一步比较超说明书使用靶向药物的精准治疗与索拉非尼标准治疗的差别，寻找索拉非尼药敏标志物并采用cfDNA动态监测进行验证。通过本研究，我们将系统探讨基因组变异指导肝癌靶向治疗的临床转化可行性，为未来开展肝癌“伞式”精准医学临床试验积累初步数据，为改善肝癌病人总体预后奠定基础。

肝癌靶向治疗对改善中晚期肝癌病人的整体预后意义重大。课题组从肝癌的基因组变异入手，寻找肿瘤特异性的遗传学改变，探索靶向药物超说明书使用，改善肝癌靶向治疗的疗效。项目在研期间，取得如下成果：（1）系统研究肝癌基因突变图谱与生物学特征和预后的相关性，首次发现了BAP1基因是肝癌中的高频突变基因，BAP1的低表达与不良预后显著相关，提示BAP1是肝癌靶向治疗的潜在位点。（2）首次揭示了肿瘤相关中性粒细胞在参与构成肝癌肿瘤微环境，促进肿瘤复发转移等方面的重要作用。证实了肿瘤相关中性粒细胞是预测肝癌患者预后的独立预测指标，可用于临床筛选高危复发患者和指导术后治疗，为肝癌的靶向治疗提供具体的肿瘤微环境研究思路。（3）系统研究与靶向药物治疗敏感相关的基因变异，发现了CCND1拷贝数扩增是肝癌中与靶向治疗相关的高频基因变异，提示CCND1拷贝数扩增可增敏帕博西林靶向治疗肝癌。（4）首次构建了肝癌特异性靶向深度测序方案，高效挖掘肝癌基因组变异。（5）基于肝癌公共数据库和病人队列研究发现BIRC3可促进肝癌侵袭转移，提示BIRC3可能是肝癌靶向治疗的潜在位点。通过本课题的以上研究，系统探讨了基因组变异指导肝癌靶向治疗的临床转化可行性，为未来开展肝癌“伞式”精准医学临床试验积累初步数据，为改善肝癌病人总体预后奠定基础。

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