分子靶向药物在肝细胞癌中的应用

手术切除和肝移植仍然是肝细胞癌(HCC)的治疗首选.对于不适宜手术切除的晚期HCC,传统的化疗并不能改善患者的预后.分子靶向药物的出现为晚期HCC的治疗提供了新的治疗手段.多靶点抑制剂、血管内皮生长抑制剂、单克隆抗体等分子靶向药物已经在HCC中广泛研究和应用.     

分子靶向药物在肝细胞癌治疗中的临床研究进展

肝癌是全球第六大常见的恶性肿瘤,也是第四大肿瘤相关死亡原因,其中肝细胞癌（hepatocellular carcinoma,HCC）占90%,且80%以上的HCC发生在肝炎和肝硬化等患者中。对于HCC的治疗方面,仅20%的HCC患者可进行手术切除、肝脏移植或射频消融治疗,而晚期HCC患者无法进行根治性治疗,其生存率也逐渐下降。近年来,分子靶向药物治疗已成为研究热点,该类药物可通过特异性的与致癌位点靶向结合而发挥抗癌作用。目前,抗HCC的靶向药物主要分为一线药物与二线药物,其中一线药物主要包括索拉非尼、仑伐替尼,二线药物主要包括瑞戈非尼、卡博替尼及雷莫芦单抗等。本文对此类分子靶向药物在HCC治疗中的临床研究进展进行综述。      

含奥沙利铂化疗方案治疗晚期原发性肝细胞癌的研究进展

索拉非尼是目前唯一被多国批准的治疗晚期原发性肝细胞癌（HCC）的分子靶向药物,但其对生存期改善有限,最终出现病情进展。近几年,含奥沙利铂的化疗方案显示出良好的临床疗效,且患者耐受性可,为晚期 HCC 患者提供了新的治疗选择。     

肝细胞癌的靶向及免疫治疗新进展

肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一, 在我国的发病率及病死率居高不下。自从索拉非尼开辟了HCC靶向治疗的新时代, 全球的药物研发人员在HCC系统治疗上的探索做出了许多的努力与贡献。近年来, 新型分子靶向药物、免疫检查点抑制剂及其联合治疗方案在晚期HCC中进行了许多大样本、国际多中心临床试验。结果显示, 免疫联合靶向以及双免疫联合的治疗效果相较于靶向或免疫单药具有显著的优势, 在延长生存期、改善患者生命质量的同时也具有令人满意的安全性。     

非小细胞肺癌分子靶向治疗标志物研究进展

肿瘤分子靶向治疗是指以肿瘤发生发展相关的关键分子作为靶点，利用抑制剂、阻断剂、抗体等药物进行抗肿瘤治疗的手段。分子靶向治疗具有特异性强、副作用小等特点，已成为非小细胞肺癌（non-small cell lung cancer，NSCLC）治疗领域的研究热点之一。目前针对NSCLC已上市的分子靶向药物主要包括癌基因分子靶向药物、抗血管生成药物、免疫靶向治疗药物以及多靶点抑制剂等。本文主要阐述不同分子靶向药物的作用机制、疗效及获益人群。     

晚期肝细胞癌的系统治疗现状及研究进展

摘 要：肝细胞癌（hepatocellular carcinoma，HCC），是一种发病率和死亡率高、预后差且易复发和转移的消化系统恶性肿瘤。以靶向治疗和免疫治疗为主的系统治疗在晚期HCC一线治疗中疗效肯定。靶向治疗联合免疫治疗可有效延长患者生存期，改善预后，中药辅助治疗也在综合抗肿瘤治疗中发挥作用。病因治疗和新的抗HCC作用靶点也是肝细胞癌领域的研究热点。全文主要围绕晚期HCC的靶向治疗、免疫治疗等系统治疗以及病因和新作用靶点研究的现状及进展进行综述。     

乳腺癌抗Her-2治疗进展

分子靶向药物与细胞毒药物相比具有选择性高、毒副反应低的优点,成为肿瘤治疗领域的研究热点。目前乳腺癌分子靶向治疗主要为抗Her-2和抗血管生成。赫赛汀、帕妥珠单抗、T-DM1等新的抗Her-2药物给患者带来了明显的生存获益和更多的选择。本文对乳腺癌抗Her-2治疗的研究进展进行综述。     

肝细胞癌治疗药物研究进展

肝细胞癌（HCC）死亡率高，晚期治疗手段有限，生存期短，对多种化疗药物易产生多药耐药。近年来HCC的分子靶向药物研究取得到了很大的进展，且与其它化疗药物联合作用有着很好的研究前景。本文对目前肝细胞癌的治疗药物进行了归纳与阐述，深入探讨各类药物在未来发展的潜力以及可能面对的挑战，为延长晚期肝癌生存期寻求有效的综合治疗方案。     

乳腺癌靶向药物的最新进展

随着分子生物学研究进展,靶向治疗已经进入一个新的时代。分子靶向治疗作为乳腺癌治疗的新领域已被广为重视。这些药物包括抗HER-2靶向药物、血管生成抑制剂、酪氨酸激酶抑制剂、聚ADP-核糖聚合酶（poly—ADP—ribose polymerase,PARP）抑制剂等。这些靶向药物的涌现不仅丰富了乳腺癌治疗的理论和实践,而且改变了临床治疗的思维模式和行为模式。本文主要对乳腺癌分子靶向药物的最新进展作一综述。     

分子靶向抗肿瘤药物临床应用

分子靶向抗肿瘤药物有独特的靶向抗肿瘤作用，在当前临床治疗中已发挥一定作用，并显示出良好的应用前景。主要有抗信号转导药物、抗血管生成药物、肿瘤耐药逆转剂及以细胞膜分化抗原为靶点的药物等。现就这些分子靶向药物的临床应用与目前研究进展作一综述。     

Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma

It is well appreciated that hepatocellular carcinoma (HCC) represents one of the most challenging malignancies of worldwide importance. In fact, HCC is the fifth most common cancer and the third most common cause of cancer-related death globally. The incidence rates for HCC in the U.S. and Western Europe have been rising. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed, molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, such as renal cell carcinoma, there has been renewed interest in developing novel systemic therapy in HCC. At the recent Annual Meeting of the American Society of Clinical Oncology, results of a phase 3, randomized, placebo-controlled trial were presented in which sorafenib demonstrated improved survival in patients with advanced HCC. This landmark study represents the first agent that has demonstrated an improved overall survival benefit in this disease and sets the new standard for first-line treatment of advanced HCC. For this review, the author concisely summarized the current status of molecularly targeted agents that are under clinical development in advanced HCC.     

Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be?

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC.     

Hepatocellular carcinoma: the role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy

Hepatocellular carcinoma (HCC) is a disease that requires multidisciplinary management. There has been no widely accepted standard for systemic therapy for this disease until recently. This article briefly discusses the management of earlier stage HCC, then focuses on newer agents with promise, particularly sorafenib, a drug that appears to be the new standard of care for advanced disease.     

Traitement systémique du carcinome hépatocellulaire

Systemic cytotoxic treatments provide marginal benefit in unresectable or metastatic HCC. With the arrival of molecularly targeted agents, there has been renewed interest in developing novel systemic treatments for HCC. For the first time, results of a phase III randomized, placebo-controlled trial were recently presented in which sorafenib demonstrated improved survival in patients with advanced HCC. Therefore, sorafenib is now the new standard for the first-line treatment of advanced HCC. The identification of predictive factors and the search for new molecules remain major challenges for this poor prognostic disease.     

HCC and angiogenesis: possible targets and future directions

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.     

Current approach in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of the disease. There are two leading types of treatment: local and systemic. Surgical resection and liver transplantation constitute the most appropriate local treatments and are considered the only real possibility for recovery. Other local approaches include: radiofrequency ablation, percutaneous ethanol ablation, hepatic endoarterial chemoembolization and intrahepatic radiotherapy (SIRT: selective internal radiation therapy). These last treatments are used to control the disease when surgery or transplantation is not achievable; in some cases they are able to prolong survival while they constitute mainly a palliative treatment. Systemic treatments include: chemotherapy, immunological and hormonal therapies and, more recently, the introduction of new specific molecular target drugs. At the moment, in this group, the only drug that has given positive results during phase III trials (SHARP study) is Sorafenib. Sorafenib represents the only primary systemic therapy that has demonstrated, unlike the other treatments previously described, an increase in survival rate in patients affected with advanced HCC. Currently, other studies are taking place that are further developing the potential of this drug. These studies, including phase III trials, are directed in order to test the activity and safety of new emerging drugs with targeted activity. Examples of these new agents are: Sunitinib, Gefitinib, Cetuximab, Bevacizumab and Erlotinib.     

Current status of molecularly targeted therapy for hepatocellular carcinoma: basic science

Conventional systemic chemotherapy has been developed with so-called anti-cancer agents, essentially screened for cytotoxicity to cultured cancer cells. However, in patients with hepatocellular carcinoma (HCC), the role of chemotherapy is quite limited because most anti-cancer agents are ineffective and relatively toxic to HCC patients with chronic liver diseases. On the other hand, accumulated understanding of the molecular mechanisms regulating cancer progression has led to novel development of molecularly targeted therapies with cytostatic agents. Recently, a phase III clinical trial revealed a multi-kinase inhibitor, Sorafenib, as the first agent leading to improved overall survival of patients with advanced HCC. A new era of HCC treatment has arrived, based on identification of deranged signaling pathways of cancer cells or their microenvironment. This review summarizes the molecular hallmarks of HCC with a focus on angiogenesis, growth signals, and mitotic stress, and a novel concept “synthetic lethality” for the targeted therapy strategy.     

Recent update on comprehensive therapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The treatment methods for HCC are diverse, mainly including surgical resection, ablation, and liver transplantation. The curative effect can be achieved only for early stage HCC, and it is easy to recur and metastasize after surgery, with a 5-year recurrence rate as high as 70%. Most patients with HCC are in the middle and advanced stage at the time of diagnosis and lose the chance of surgical resection. In recent years, with the in-depth study of the pathogenesis of HCC and the progress of medical science and technology, the systemic treatment of advanced HCC has made a breakthrough. At present, multidisciplinary comprehensive treatment including targeted therapy and immunotherapy has become an effective strategy and inevitable trend for the treatment of advanced HCC. Combined therapy has greatly improved the prognosis of HCC patients and opened up a new milestone in the treatment of this malignancy. In this article, we focus on the treatment progress of advanced HCC to further guide clinical practice.     

Novel molecular targets in hepatocellular carcinoma

Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.     

Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives

Improving the overall survival for patients with advanced hepatocellular carcinoma (HCC) requires development of effective systemic therapy. Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced HCC remains poor and the benefits with sorafenib are modest. In the past few years, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC. While the initial efforts are focusing on anti-angiogenic therapy, other agents targeting the epidermal growth factor-receptor, mammalian target of rapamycin (mTOR), hepatocyte growth factor/c-Met among others have entered HCC clinical trials. Combining different molecularly targeted agents or combining targeted agents with chemotherapy represent other strategies under investigation. This review will attempt to summarize the current status of other molecularly targeted agents or regimens beyond sorafenib under development in advanced HCC and the future perspectives.