肝细胞癌相关分子靶向治疗研究进展

外科手术仍然是治疗肝细胞癌(HCC)最主要的手段,但外科手术的低切除率和高复发率,迫使人们深入研究HCC的发病、转移和侵袭过程中的分子机制,来开发更有效的早期诊断和治疗手段。通过复习相关文献,系统总结了部分HCC相关的主要信号通路及对应的分子靶向治疗研究新进展,包括PI3K/AKT/m TOR信号通路、RAS/RAF/MEK/ERK信号通路、VEGF/VEGFR、PDGFR、FGFR信号通路等,并对HCC分子靶向治疗的研究方向进行了展望。     

肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.     

肝细胞癌的分子靶向治疗研究

原发性肝癌[主要为肝细胞癌(HCC)]患者病情复杂,宜根据病变的具体情况和各种治疗方法的不同特点和适应证选择最佳个体化方案。治疗方法的选择应依据肿瘤的大小和数目、肿瘤侵袭的部位和范围、静脉癌栓和远处转移情况、患者肝功能代偿程度以及全身状况全面衡量而决定。根治性治疗     

Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.     

Molecular targeted therapy for hepatocellular carcinoma: bench to bedside

According to the International Agency for Research on Cancer, approximately 670,000 new cases of hepatocellular carcinoma (HCC) developed in 2005, making it the fifth most common cancer and third most common cause of cancer-related death worldwide. HCC is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as EGFR, Ras/Raf/MEK, PI3K/mTOR, HGF/MET, Wnt, Hedgehog and apoptotic signaling pathway. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. It has been proposed that signaling pathway disruption in cancer can be grouped in six function capabilities, some of which need to be altered for cancer development: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis and tumor invasion and metastases. The aim is to integrate these concepts into the molecular pathogenesis of HCC. It has also been proposed that there are common disturbances universal to all liver cancers on top of the more specific mechanisms. Based on this basic research, a molecular targeted agent has recently been developed. There have been no effective chemotherapeutic agents for advanced HCC. Sorafenib, an oral multikinase inhibitor, has set a milestone in the management of HCC in that it is the first agent to significantly improve the overall survival in patients with advanced HCC in a double-blind, placebo-controlled, phase III study. Clinical trials testing new agents for first- and second-line agents, as well as in combination with existing treatment options such as transarterial chemoembolization or arterial infusion chemotherapy, are ongoing. The results of these trials are therefore eagerly awaited.     

Molecular targeted therapies in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.     

Molecular targeted therapy in hepatocellular carcinoma: present achievements and future challenges

Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib's role and safety profile, especially in the treatment of patients with suboptimal liver function.     

Evaluating the current surgical strategies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Despite careful surveillance programs and the development of antiviral therapy for hepatitis virus infection, the occurrence rate of HCC remains high. Liver resection and liver transplantation are mainstay curative treatments. Most patients with HCC have impaired liver function, and surgical treatment is always accompanied by the risk of decompensation of the remnant liver, especially when the volume of the remnant liver is too small and the liver function too low to meet metabolic demands. The mortality of liver resection has dramatically decreased over the last three decades from 20% to less than 5% due to the accumulation of knowledge of liver anatomy, perioperative management and preoperative assessment of liver function. Here we provide an overview of the multidisciplinary treatments and current standard treatment strategies for HCC, to explore the possibility of expanding surgical treatments beyond the current standards.     

原发性肝癌的分子靶向治疗策略

原发性肝癌(简称肝癌)是严重危害我国人民健康的重大疾病,具有高发病率、高转移率、高复发率和高病死率的特点.探索新的更有效的肝癌治疗方法一直是研究的热点,也是对目前以外科手术切除和肝移植为主的肝癌综合治疗体系的有益补充和改进.     

靶向药物治疗肝细胞癌的最新进展

靶向药物对于肝细胞癌的治疗效果在临床上已经被广泛证实。随着科学技术的发展,越来越多的靶向药物相继出现。近期,瑞格菲尼、ramucirumab等靶向药物在相应的临床实验中也表现出了相当的潜力。更多的二线候选药物,比如c-Met抑制剂tivantinib与cabozantinib、VEGFR-2抑制剂ramuciruma临床试验正在进行。总结了近几年靶向药物治疗肝细胞癌的试验数据及最新进展,为下一步临床试验及治疗提供参考意见。     

原发性肝癌分子靶向治疗研究进展

分子靶向治疗为肝癌的治疗提供了新的手段,他能够特异性的作用于肿瘤发生发展中起关键作用的靶分子及其调控的信号传导通路, 从而达到治疗肿瘤的目的. 在肝癌分子靶向治疗的临床试验中, 靶向表皮生长因子受体、血管内皮细胞生长因子和多靶点抑制剂的药物治疗已经显示出了潜在的疗效和良好的发展前景. 本文针对原发性肝癌的分子靶向治疗理论基础及临床研究进展进行综述.     

Novel approaches for molecular targeted therapy against hepatocellular carcinoma

Systemic chemotherapy using a multitargeted tyrosine kinase inhibitor is an established treatment for advanced‐stage tumors in various organs. Comprehensive genomic analyses using next‐generation sequencing technology revealed the intra‐ and intertumor heterogeneity of human hepatocellular carcinomas (HCCs), and provided evidence for the use of therapeutic agents effective against multiple targets in tumor cells. Recently, the efficacy and safety of a multitargeted tyrosine kinase inhibitor, lenvatinib, was confirmed by a randomized global phase III trial; thus, lenvatinib was approved as first‐line therapy for HCC, providing a new therapeutic option for patients at an advanced stage. In this article, we introduce the application of molecular targeted therapy using lenvatinib and discuss future aspects of therapeutic options for advanced HCC.     

肝细胞癌的分子靶向治疗

肝细胞癌(hepatocellular carcinoma,HCC)是人类第5大恶性肿瘤,死亡率极高.在我国,HCC的治疗已取得显著进展,但总体发病率和死亡率尚无明显改观,对于不适宜手术切除的晚期HCC,现有的药物治疗并不能改善患者预后,进一步提高疗效仍面临严峻挑战.所以,发现新的靶向治疗药物或新的靶点对HCC的早期诊断、化学预防以及治疗显得尤为重要.目前从对HCC发生、发展的分子机制的研究中,人类已发现了多个潜在分子靶点.这些靶点大部分为酪氨酸激酶受体激活的信号传导通路,包括:Raf/MEK/ERK,PI-3K/Akt/mTOR和Jak/Stat等.以索拉菲尼、舒尼替尼等为药物代表的多靶点、多激酶抑制剂治疗HCC更是受到高度关注.本文主要介绍HCC潜在的分子靶点以及常用靶向药物的临床进展.     

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。     

关注原发性肝癌的靶向治疗研究

近年来,肿瘤的靶向治疗取得很大进展,成为肿瘤临床研究的热点,并对某些肿瘤取得明显疗效。针对原发性肝癌(下称肝癌)的靶向治疗亦引起进一步重视。肝切除术是目前肝癌治疗最有效的根治性手段。对于不能手术切除的肝癌可考虑从器官(组织)、细胞和分子三个水平实施靶向治疗。     

靶向时代肝细胞癌的介入治疗

原发性肝细胞癌(hepatocellular carcinoma,HCC)的发病率逐年上升,对于不适于肝移植或手术切除的肝内病灶,肝动脉化疗栓塞(transarterial embolization,TACE)是最主要的治疗方法。随机试验已证实该疗法能为HCC患者带来临床获益。荟萃分析显示,与保守治疗相比,TACE可改善HCC患者的临床结局。然而,TACE治疗后,血管内皮生长因子水平的上升会增大疾病进展的几率。分子靶向药物索拉非尼(sorafenib)的引入改变了HCC治疗的现状,其可以阻断多种细胞表面及细胞内与增殖和血管生成相关的受体。已有2项国际研究(SHARP和Asia-Pacific)证实,索拉非尼可有效延长晚期HCC患者的疾病进展时间和生存时间。TACE联合索拉非尼通过阻断TACE术后血管生成信号的激活,有望改善治疗结局。已有许多临床研究探索二者联合在HCC治疗中的应用。初步资料显示,联合疗法安全可行。尽管如此,目前尚不推荐在临床研究的环境之外采取联合治疗。随着临床研究的深入,相关资料将进一步指导临床。     

缺氧诱导因子-1分子组成、活化机制及肝癌靶向治疗

肝癌是世界常见恶性肿瘤之一,其发生是多中心,多病因和多基因参与的复合过程.其目前的治疗仍以手术切除为主,而肝癌确诊时大多已属中晚期,治疗效果很差.因此开发新的分子标志物早期诊断肝癌和寻找新的基因治疗靶点成为肝癌研究的热点.缺氧诱导因子-1(HIF-1)参与肝癌发生、发展、转移及术后复发的多个环节,对肝癌的早期诊断和分子靶向治疗具有潜在的应用前景.本文就HIF-1的分子组成、活化机制以及与肝癌靶向治疗相关进展作一综述.     

Molecular therapy and prevention of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, toxins (alcohol, aflatoxin B1) and various inherited metabolic liver diseases, such as hemochromatosis and alpha-1-antitrypsin deficiency. Central to the molecular pathogenesis of HCC are mutations of various genes and genetic/chromosomal instability that result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. Alterations in the structure or expression of several tumor suppressor genes and oncogenes have been described. In addition, mechanisms leading to genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation appear to be involved. The prognosis of HCC patients is generally very poor. Most studies have shown a five-year survival rate of less than 5% in symptomatic patients. HCC has been found to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCC revealed a long-term survival of patients only with small asymptomatic HCC that could be treated surgically or nonsurgically. For patients with advanced symptomatic HCC, novel therapeutic strategies such as gene therapy are urgently needed. Apart from exploring and refining new HCC treatment strategies, the implementation of the existing measures or the development of novel measures to prevent HCC is most important. Primary HCC prevention could have a major impact on the incidence of HCC. Further, secondary prevention of a local recurrence or of new HCC lesions in patients after successful surgical or nonsurgical HCC treatment is of paramount importance and is expected to significantly improve disease-free and overall survival rates of patients. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually complement or in part replace the existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reduced HCC incidence and an improved clinical outcome for patients with HCC, one of the most devastating malignancies worldwide.