Peter R. Galle（ MD， PhD ）

　　德国美因兹大学医院院长，世界肝癌学会（ILCA）财政部长，AASLD、EASL成员，研究方向为肝脏中的细胞凋亡、肿瘤细胞的免疫逃逸等。已发表超过350篇学术文章。

　　困境：

　　The knowledge that signaling control proliferation and angiogenesis has， after years of therapeutic nihilism， resulted in the development of the multikinase inhibitor sorafenib as the first agent to demonstrate a significant improvement in the survival of patients with advanced hepatocellular carcinoma (HCC). However， survival benefits on sorafenib treatment remain modest in clinical practice and toxicity is an issue. This has stimulated further clinical trials on other targeted agents but unfortunately， sorafenib proved to be no low-hanging fruit. So far， four phase III trials in first-line and one phase III trial in second-line therapies have failed as they were unable to show non-inferiority or superiority when compared to sorafenib.

　　有关肿瘤血管生成和肿瘤细胞生存、增殖的信号调控理论为第一个多激酶抑制剂索拉非尼的问世奠定了基础，改善了晚期肝癌患者的生存率。然而，临床上索拉非尼对患者的生存获益依然不尽如人意，且它的毒性作用仍是一个问题，这引发了人们对其他靶向治疗药物的临床研究，但至今没取得突破性进展。截至目前，关于新靶向药物作为一线药物和二线药物的5项Ⅲ期临床研究结果均未显示出较索拉非尼更好的疗效，以失败告终。

　　出路：

　　One explanation for this barrier in the development of therapeutic strategies in HCC is the general lack of available tumor tissue. Current guidelines do not ask for mandatory biopsies if radiological imaging shows typical features of HCC as is the case in most patients. However， tumor tissue would help identify subgroups of patients benefitting from novel strategies. The lack of tissue in HCC is in contrast to other tumors such as lung cancer where molecular subgrouping is already a reality. In this regard it is worthwhile mentioning that the first biopsy-based clinical trial in phase III has just started recruiting - the analysis of the c-MET inhibitor tivantinib as a second-line treatment in patients with HCC and high level expression of MET in immunohistochemistry.

　　Besides the characterization of predictive signatures to subgroup patients with HCC， understanding and unraveling the characteristics of stem cell biology in HCC may pave the way towards novel strategies such as cancer stem cell markers.

　　Another novel path is therapeutic interference with epigenetic mechanisms. Epigenetic alterations contribute to tumor development， progression and failure of therapy. The pan-HDAC inhibitor， resminostat， has been shown to reset drug-sensitivity in sorafenib-resistant patients and thus might be a tool to maximize sorafenib’s efficacy until new druggable targets of clinical relevance have been identified.

　　对于肝癌治疗面临的这种困境，解释之一是缺乏肝癌的组织学检查。目前的相关肝癌诊疗指南认为，在影像学上有典型肝癌征象的情况下，不应对患者进行强制性穿刺活检。然而，肿瘤组织学检查却能帮助我们发现哪些患者有可能从新治疗策略中获益。例如，肺癌的分子学水平的亚组分型早已成为惯例。因此，值得一提的是，首个以组织活检为基础的Ⅲ期临床研究--c-MET抑制剂（tivantinib）作为二线药物治疗MET免疫组化水平高表达的肝癌患者的研究项目已经开始招募。

　　除了对肝癌患者预测性特征的亚组分型，理解肝癌干细胞的生物学特征也为新的治疗策略指明方向。

　　还有一条途径是对表观遗传机制的治疗干预。表观遗传变化促进肿瘤的发生发展，关系到抗肿瘤治疗的成败。已证明，全组蛋白去乙酰化酶抑制剂，resminostat，能够重置索拉非尼耐药患者的药物敏感性。在新一代靶向治疗成功之前，它或许能使索拉非尼的功效最大化。