晚期原发性肝癌靶向及免疫治疗的研究进展

肝细胞癌（HCC）是原发性肝癌的主要组织学类型，占原发性肝癌的75%～85%。由于HCC起病隐匿，大多数患者初诊时即为晚期，手术切除、射频消融、肝动脉化疗栓塞等治疗效果有限，5年生存率较低。随着肿瘤分子信号通路和肿瘤微环境研究的不断深入，靶向治疗成为晚期HCC临床研究的热点，相继研发出了一系列靶向药物，如一线治疗的索拉非尼、仑伐替尼、多纳非尼以及二线治疗的瑞戈非尼、卡博替尼、雷莫芦单抗。除了靶向治疗外，近年来免疫检查点抑制剂在晚期HCC治疗中亦取得了突破性进展，相继研发出了一系列免疫检查点抑制剂，如纳武利尤单抗、帕博利珠单抗、卡瑞利珠单抗。这些新型靶向药物及免疫检查点抑制剂相继被批准用于晚期HCC治疗，为患者带来了更多的临床获益。     

肝细胞癌的靶向治疗

近年来,随着肝细胞癌(HCC)分子机制研究深入,靶向治疗也得到了迅猛发展,在延缓和改善患者疾病进展和预后方面作出了巨大贡献。由于HCC的发病机制错综复杂,单一的分子靶向治疗总体临床收益并不理想。因此,近年来靶向联合其他治疗方式的新方案不断出新,并取得了令人鼓舞的成果。就HCC分子靶向治疗药物、研究现状及临床联合应用治疗进展予以简要总结。     

分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在肝细胞癌中的应用

肝细胞癌(HCC)是最常见的恶性肿瘤之一,发病隐匿,发展迅速,高复发的特点导致HCC患者长期生存面临巨大挑战。分子靶向药物与免疫抑制剂在HCC治疗中成为研究的热点,大量临床试验发现,联合治疗取得了不错的疗效。主要介绍了分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在HCC中的应用,指出当前HCC治疗的最新研究热点在于系统治疗或局部治疗相关的联合治疗。     

分子靶向药物治疗肝细胞癌的研究进展

肝细胞癌(HCC)严重威胁着人类的生命健康。在临床治疗中,HCC治疗策略的选择越来越备受关注,随着对HCC发病机制的不断研究及分子生物学技术的飞速发展,分子靶向抗肿瘤药物治疗晚期HCC成为研究热点,并在临床实践中取得了显著疗效。回顾了近几年HCC分子靶向治疗药物最新临床应用研究进展及出现的相关问题,并针对其治疗策略的未来焦点进行展望,为应用研究和临床治疗HCC提供新的方向和参考。     

肝细胞癌的分子靶向治疗

肝细胞癌(hepatocellular carcinoma, HCC)死亡率居所有肿瘤的第二位,且近年在我国有上升趋势.因其发病隐匿、进展快、预后差,一直是研究的热点和难点.近10年来, HCC的治疗方法有了显著性进展,尤其是分子靶向药物的使用和研究,开启了HCC治疗方法的新阶段.本文就目前HCC发生发展相关信号通路及潜在分子靶点的研究现状、分子靶向治疗药物临床使用状况以及新药研发进展做了比较详细地叙述.     

肝细胞癌的免疫治疗

在过去的10年里,肝细胞癌(HCC)系统治疗的进步归功于分子靶向治疗的应用及免疫治疗的提高。HCC所处的免疫抑制微环境使肝癌细胞逃逸免疫系统的攻击,这亦为肝癌发展的重要原因,通过提高针对HCC的免疫杀伤能力,纠正免疫抑制状态是HCC免疫治疗的策略。HCC特异性抗原为基础的肿瘤疫苗治疗、基因工程改造的T淋巴细胞治疗、免疫检查点抑制剂的基础研究及临床转化使免疫治疗效果较过去有了显著提高。免疫治疗联合其他抗肿瘤治疗方法如局部消融、分子靶向治疗或肿瘤疫苗等综合治疗模式值得进一步探索。     

IGF-1受体介导的信号通路与肝癌靶向治疗

胰岛素样生长因子家簇（IGFs）与肝癌（HCC）发生发展、转移和耐药相关。IGF-ⅠR和IGF-Ⅱ在HCC进展过程中过量表达,IGF-ⅠR与IGF-Ⅱ结合导致自身酪氨酸激酶磷酸化,激活下游信号通路,使肝细胞恶性转化潜力增加,已证实IGF-ⅠR是HCC分子治疗的理想靶点。本文概述了IGF-ⅠR在HCC发生发展过程中表达、作用及所介导的肝癌靶向治疗进展。     

非手术治疗原发性肝癌研究进展

肝细胞癌（HCC）是世界范围内第五大常见肿瘤,为肿瘤相关死亡的第三大常见原因。由于HCC 早期症状隐匿,大多数患者在确诊时已是中晚期,失去了接受治愈性治疗的机会。目前,HCC的非手术治疗方法很多,包括介入栓塞化疗、消融、放射治疗、化疗和分子靶向治疗等。现有治疗方法的单独或组合应用已被证明能够控制肿瘤生长,延长生存时间,提高生活质量。     

叉头转录因子家族在肝细胞癌中的作用机制及其作为治疗靶点的前景

肝细胞癌(HCC)是最常见的恶性癌症之一,发病率和病死率一直居高不下,预后很差。叉头框(FOX)转录因子家族可调控细胞的生长、分化及组织发育,在肿瘤中具有重要的生物学作用。综述了FOX家族分子表达与HCC发生发展及预后的关系,分析了FOX在HCC进展中发挥作用的机制,提出FOX家族分子有望成为HCC治疗的新靶点。     

肝细胞癌的分子靶向治疗进展

肝细胞癌是临床常见的恶性肿瘤,传统的手术及化疗难以使患者受益。近年来,分子靶向治疗对一些肿瘤已取得突破性进展,肝癌的分子靶向治疗也在临床试验中取得了令人鼓舞的结果。本文针对肝癌的分子靶向治疗的研究进展做一综述。     

Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC.     

Management of advanced hepatocellular carcinoma in the era of targeted therapy

Systemic chemotherapy has had a disappointing track record in the management of advanced hepatocellular carcinoma (HCC). Single‐agent doxorubicin produces a response rate of 10–15%, but without any survival benefit, and combination chemotherapy has also yielded unimpressive results. With recent advances in the knowledge of hepato‐carcinogenesis, there has been encouraging development in the systemic therapy of advanced HCC patients, and particularly in the targeted therapy of advanced HCC. Among the newly identified targets, exciting results have been shown in targeting the anti‐angiogenic pathway and the Raf/mitogen‐activated protein kinase pathways. Bevacizumab, both as a single agent and in combination with other agents, has shown initial encouraging activity in treating advanced HCC. More recently, single‐agent sorafenib, a putative multitargeted kinase inhibitor, has shown to prolong the overall survival of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study. Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC. In addition, however, promising early results have been reported for other molecular‐targeted drugs including erlotinib and sunitinib. Future progress seems likely to depend on using controlled clinical trials to optimize synergistic combination treatments.     

Targeted therapy of hepatocellular carcinoma: present and future

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.     

Targeted and immune therapies for hepatocellular carcinoma:Predictions for 2019 and beyond

Systemic therapy for hepatocellular carcinoma(HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However,development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1 st line and 2 nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed.On the other hand, clinical trials of 4 agents(regorafenib, lenvatinib,cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible(regorafenib and lenvatinib) or underway(cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization(TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib(TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early,intermediate and advanced stage, is expected to be changed drastically in the very near future.     

Molecular Therapies in Hepatocellular Carcinoma: What Can We Target?

Numerous signaling pathways, such as Ras/Raf/MAPK, have been implicated in hepatic carcinogenesis. There are at least 35 combination therapy studies for advanced stage hepatocellular carcinoma (HCC) ongoing, and numerous reagents are being tested targeting novel signaling cascades. The management of HCC has changed substantially in recent times, and the successful development of sorafenib has prompted further expansion on molecular targeted therapies to potentially inhibit different pathways in hepatocarcinogenesis.     

Molecular targeted therapy for hepatocellular carcinoma in the current and potential next strategies

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its incidence is still increasing. While the primary curative treatment for HCC is surgical resection, a major obstacle for the treatment of HCC is the high frequency of tumor recurrence even after curative resection. Effective palliative treatment is hindered by the evidence that HCC is frequently resistant to conventional chemotherapy and radiotherapy. Targeted therapy which specifically inhibits molecular abnormalities has emerged as a novel approach for the innovative and effective medical treatment of malignancies. In order to fulfill this promise there is an urgent need to identify the optimal targets for the treatment of HCC. A multi-kinase angiogenesis inhibitor, sorafenib, has been revealed as the first agent to show favorable overall survival in patients with advanced HCC. A new era of HCC treatment has arrived, but there has been limited improvement in survival benefits with the status quo. This review summarizes molecular targeted therapy for HCC, with a focus on angiogenesis, growth signaling, and mitosis, as well as a promising concept, ??cancer stemness?? for the current and potential next strategies of HCC treatment.     

中晚期肝癌临床治疗进展

肝癌的发病隐匿,早期诊断困难,进展较快,临床上仅有不足30%的患者就诊时可获得手术治疗的机会,因此非手术疗法是中晚期肝癌的主要治疗方式。总结了几种主要的非手术治疗方式———血管介入治疗、分子靶向和化疗药物治疗、放疗以及局部消融治疗在肝癌治疗中的地位。认为尽管综合治疗已成为肝癌治疗的共识,但是他们在综合治疗中的地位及次序等仍未形成共识,还需要进行更多的临床研究,从而为中晚期肝癌患者的治疗提供更好的选择。     

Treatment for hepatocellular carcinoma in Japan over the last three decades: Our experience and published work review

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related mortality worldwide. In the last few decades, there has been a marked increase in therapeutic options for HCC and epidemiological characteristics at HCC diagnosis have also significantly changed. With these changes and advances in medical technology and surveillance program for detecting earlier stage HCC, survival in patients with HCC has significantly improved. Especially, patients with liver cirrhosis are at high risk of HCC development, and regular surveillance could enable early detection of HCC and curative therapy, with potentially improved clinical outcome. However, unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation, surgical resection or ablative therapies). Locoregional therapies such as radiofrequency ablation, percutaneous ethanol injection, microwave coagulation therapy and transcatheter arterial chemoembolization play a key role in the management of unresectable HCC. Currently, molecular‐targeted agents such as sorafenib have emerged as a promising therapy for advanced HCC. The choice of the treatment modality depends on the size of the tumor, tumor location, anatomical considerations, number of tumors present and liver function. Furthermore, new promising therapies such as gene therapy and immunotherapy for HCC have emerged. Approaches to the HCC diagnosis and adequate management for patients with HCC are improving survival. Herein, we review changes of epidemiological characteristics, prognosis and therapies for HCC and refer to current knowledge for this malignancy based on our experience of approximately 4000 HCC cases over the last three decades.     

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

射频消融在肝癌多学科综合治疗中的应用

以射频消融（RFA）为代表的局部消融治疗已成为肝癌的重要治疗手段,在肝癌治疗中得到广泛的应用。其主要适应证为肿瘤单发、直径≤5 cm;或者肿瘤2～3个、最大直径≤3 cm。数个临床研究表明射频治疗小肝癌的效果与手术切除相当,国内外多个肝癌临床治疗指南已经将射频与手术切除一样,并列为小肝癌的根治性治疗方法。临床上RFA常常与手术切除、血管介入、瘤内无水酒精注射术、放射治疗、化疗、靶向药物治疗、免疫生物治疗等方法联合应用,在肝癌多学科综合治疗领域中起着越来越重要的作用。