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。     

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。     

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     

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。     

小分子靶向药物治疗肝细胞癌的研究进展

小分子靶向药物索拉菲尼通过抗肿瘤细胞增殖、抗血管生成和(或)促凋亡作用,破坏肿瘤微血管、抑制肿瘤生长.Ⅱ、Ⅲ期临床研究均证实,索拉菲尼用于不能外科手术或局部区域性治疗,以及上述治疗后病情进展的肝细胞癌(HCC)患者,能显著延长患者的中位总存活期,获得更高的疾病控制率;已被多个国家批准作为首个治疗HCC的分子靶向药物用于...     

胃肠道间质瘤分子靶向治疗的不良反应及对策

胃肠道间质瘤是胃肠道及腹腔最常见的间叶源性肿瘤。分子靶向治疗被证明对间质瘤疗效显著,但同时也会抑制正常组织细胞运作而产生不良反应。目前已批准应用于间质瘤的分子靶向治疗药物有甲磺酸伊马替尼和苹果酸舒尼替尼,另有尼洛替尼正在临床试验中。此文就胃肠道间质瘤靶向治疗中所出现的各种不良反应的产生机制、临床表现和相应措施作一综述。     

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。     

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.     

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.     

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.     

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Primary liver cancer is one of the commonest causes of death. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. For patients with unresectable or metastatic HCC, conventional chemotherapy is of limited or no benefit. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit, leading to an era of targeted agents. Many clinical trials of targeted drugs have been carried out with many more in progress. Some drugs like PTK787 showed potential benefits in the treatment of HCC. Despite these promising breakthroughs, patients with HCC still have a dismal prognosis. Recently, both a phase III trial of everolimus and a phase II clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC. Sorafenib still plays a pivotal role in advanced HCC, leading to further explorations to exert its maximum efficacy. Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances. New targeted agents such as mammalian target of rapamycin inhibitors are under investigation, as well as further exploration of the mechanism of hepatocarcinogenesis.     

Resistance to molecularly targeted therapy in non-small-cell lung cancer

The discovery of oncogenic driver gene mutations, including epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, and ret proto-oncogene (RET) fusion, has led to the development of molecularly targeted therapy for non-small-cell lung cancer (NSCLC). This therapy has changed the standard of care for NSCLC. Despite the dramatic response to molecularly targeted therapy, almost all patients ultimately develop resistance to the drugs. To understand the mechanisms of resistance to molecularly targeted agents, it is essential to understand the molecular pathways of NSCLC. Here, we review the mechanisms of resistance to molecularly targeted therapy and discuss strategies to overcome drug resistance.     

Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth,invasion,and metastasis,and enabled the development of molecular-targeted agents.To date,sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase Ⅲ randomized controlled trials,and has been approved worldwide.Phase Ⅲ clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing.Those agents target the vascular endothelial growth factor,platelet-derived growth factor receptors,as well as target the epidermal growth factor receptor,insulinlike growth factor receptor and mammalian target of rapamycin,in addition to other molecules targeting other components of the signal transduction pathways.In addition,the combination of sorafenib with standard treatment,such as resection,ablation,transarterial embolization,and hepatic arterial infusion chemotherapy are ongoing.This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways.Finally,the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed.     

Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

The incidence and mortality of hepatocellular carcinoma(HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.     

Therapeutic options for intermediate-advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies, ranking the sixth in the world, with 55% of cases occurring in China. Usually, patients with HCC did not present until the late stage of the disease, thus limiting their therapeutic options. Although surgical resection is a potentially curative modality for HCC, most patients with intermediate-advanced HCC are not suitable candidates. The current therapeutic modalities for intermediate-advanced HCC include: (1) surgical procedures, such ...