PI3K/AKT/mTOR信号通路介导索拉非尼治疗原发性肝癌耐药机制的研究进展

索拉非尼（sorafenib）作为原发性肝癌（hepatocellular carcinoma,HCC）靶向治疗的一线药物已广泛应用于临床,然而部分HCC患者对索拉非尼治疗耐药导致临床疗效欠佳,联合其他靶向药物的临床实验仍未取得突破,故深入研究索拉非尼耐药机制,逆转索拉非尼耐药对于改善肝癌治疗的预后具有重要意义。最新研究发现,PI3K/AKT/mTOR信号通路在索拉非尼耐药机制中起重要作用,本文将从PI3K/AKT/mTOR信号通路促进肿瘤血管生成、参与细胞自噬、抑制肿瘤细胞凋亡并促进其增殖、与RAS/RAF/ERK/MEK信号通路交联及其促进上皮-间质转化等几个方面,概述其在索拉非尼治疗原发性肝癌时产生耐药的机制,为进一步开发治疗原发性肝癌的新型药物提供研究方向。     

Signaling pathways in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer, and its mortality rate is the third highest after lung and colon cancer. Its incidence has significantly increased in the last two decades in close relation with the ubiquitous spread of viral hepatitis. HCC has a poor prognosis since less than 30% of newly diagnosed patients will be eligible for potential curative treatment. Molecular therapies such as sorafenib, a BRAF/ VEGFR/PDGFR tyrosine kinase inhibitor, have shown to improve survival in patients with advanced HCC. This recent success has spurred intensive research aimed at identifying aberrant activation of signaling pathways. This approach will probably aid to define previously unrecognized oncogenic addiction loops in HCC and in developing more effective targeted therapies.     

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.     

索拉非尼治疗国人晚期肝细胞癌的临床研究进展

原发性肝癌, 主要是肝细胞癌（HCC）,是我国高发、常见的恶性肿瘤,晚期患者治疗棘手、预后恶劣。我国的HCC在发病原因、生物学行为、临床特征、治疗选择和预后上,都与西方国家明显不同,积极探索适合我国HCC患者合理规范的治疗具有重要意义。分子靶向药物索拉非尼作为口服多靶点多激酶抑制剂,经国际大型临床研究证实可以延长晚期HCC患者的生存期,在我国上市应用6年多,其疗效和安全性较好,但也存在一些问题。为了合理用药,进一步提高疗效,近年来,国内学者陆续开展了一系列索拉非尼单药、联合其他药物或手段治疗国人晚期HCC的临床研究和观察。本文拟对其相关研究进展进行综述和讨论,以提供临床参考。     

Immune checkpoint inhibitors in hepatocellular carcinoma: A review of current clinical trials

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.     

Asian consensus workshop report: expert consensus guideline for the management of intermediate and advanced hepatocellular carcinoma in Asia

Hepatocellular carcinoma (HCC) is a highly prevalent disease in many Asian countries, accounting for 80% of victims worldwide. Screening programs improve the detection of early HCC and have a positive impact on survival, but the majority of HCC patients in Asia still present with advanced stage disease. The treatment outcomes of HCC are affected by multiple variables, including liver function, performance status of the patient, and tumor stage. Therefore, it is not easy to apply a multidisciplinary therapeutic approach for optimal management. At present, limited numbers of HCC patients are eligible for curative therapies such as surgery or ablation in Asia. Therefore, most patients are eligible for only palliative treatments. For optimal management, the treatment choice is guided by staging systems and treatment guidelines. Numerous staging systems have been proposed and treatment guidelines vary by region. According to the Barcelona Clinic Liver Cancer (BCLC) guideline based on evidence from randomized clinical trials, only transarterial chemoembolization (TACE) is recommended for intermediate stage HCC and sorafenib for advanced stage HCC. However, treatment guidelines from Asian countries have adopted several other therapeutic modalities such as a surgical approach, hepatic arterial infusion chemotherapy, external radiation, and their combinations based on clinical experiences for intermediate and advanced stage HCC. Although TACE is the main therapeutic modality in the intermediate stage, overall therapeutic outcomes depend on the tumor size. In the advanced stage, the prognosis depends on the tumor status, e.g. major vessel invasion or extrahepatic spread. Thus, a new staging system representing prognoses suitable for Asian HCC patients and a corresponding optimal treatment algorithm should be further investigated using evidence-based data, which will finally bring about an Asian consensus for the management of intermediate and advanced stage HCC.     

Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial

Until now, no effective systemic treatment options have been available for patients with unresectable advanced hepatocellular carcinoma (HCC). In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), patients with unresectable advanced HCC with Child–Pugh liver function class A and who had not received prior systemic therapy, received either oral sorafenib (400 mg twice daily) or placebo until radiological and symptomatic progression. The two groups of patients were well balanced with respect to baseline characteristics. The study was stopped at the second planned interim analysis because of an advantage in the median overall survival (10.7 vs 7.9 months; hazard ratio: 0.69; 95% CI: 0.55–0.87; p < 0.001) and the median time to radiological progression (5.5 vs 2.8 months; p < 0.001) in the sorafenib arm. However, sorafenib was not able to increase the time to symptomatic progression. In terms of toxicity, there were more cases of diarrhea, weight loss, hand–foot skin reaction and hypophosphatemia among the patients receiving sorafenib, the majority of which were of grade 1 or 2 severity. The SHARP trial has demonstrated that sorafenib is effective in prolonging median survival and time-to-progression in patients with advanced HCC and that it is generally well tolerated with a manageable adverse events profile.     

A narrative review of systemic treatment options for hepatocellular carcinoma: state of the art review

Hepatocellular carcinoma (HCC) is an aggressive cancer that typically develops in the setting of underlying cirrhosis of the liver. HCC commonly presents in advanced stages and if eligible orthotopic liver transplantation (OLT) and surgical resection/ablation remain as the only curative options. Prior to 2007, no systemic therapy was available that demonstrated an improvement in survival. Underlying cirrhosis and poor synthetic hepatic function provides a major challenge into effective systemic options contributing to the poor success of cytotoxic chemotherapy in HCC. The first drug to achieve clinical success was sorafenib despite the underwhelming overall survival of 3 months. Since then, other targeted therapies have shown modest benefit as well. Most recently, immunotherapy advances have come to the forefront in the management of HCC and combination therapy with immunotherapy and monoclonal antibodies have now surpassed sorafenib as first line treatment. This article will review the various approved and emerging therapies that have had a significant clinical impact and highlight the future directions and ongoing research that will hopefully translate into better outcomes in the treatment approach of advanced HCC.     

Elevated hepatocyte growth factor expression as an autocrine c‐Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer‐related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second‐line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib‐resistant cells from Huh7 and Mahlavu cell lines by long‐term sorafenib exposure. Sorafenib‐resistant HCC cells acquired spindle‐shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long‐term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c‐Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c‐Met signaling. Importantly, the combined treatment of the resistant cells with c‐Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib‐induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c‐Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c‐Met inhibitors comprise promising candidates for overcoming sorafenib resistance.     

Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide and remains to be a major global health care problem. Until 2007, no effective therapies were available for patients after failure of locoregional approaches, and the approval of sorafenib as the first systemic agent with efficacy in patients suffering from advanced HCC marked a new era in the treatment of this deadly disease. However, it took nearly 10 years until the portfolio of effective drugs finally expanded and additional substances showed activity in both first and further lines of treatment. Since their recent approval, these novel substances have substantially changed the field of palliative treatment strategies in patients with advanced HCC, and their sequential application has demonstrated their potential to significantly prolong patient survival in the palliative setting. With the recently communicated data from the first positive immuno-oncology trial in HCC, it appears highly likely that the implementation of IO concepts will result in a further improvement of patient prognosis. Although locoregional approaches remain an integral component of meaningful treatment concepts for patients with BCLC-B stage HCC, repetitive interventions bear the risk of a progressive deterioration of liver function. More than ever, in order to implement long-term therapeutic concepts and exploit the full potential of systemic treatment strategies, it is of utmost importance to maintain a fine balance between anti-tumor activity and toxicity.With an emphasis on the systemic treatment options, this review provides a summary of the most recent results from large phase III clinical trials and discusses their clinical implications.     

甲胎蛋白对索拉菲尼治疗进展期肝细胞癌的预后评价

近几年来以索拉菲尼为代表的分子靶向药物已成为进展期肝细胞癌综合治疗的热点之一,但目前对于索拉菲尼治疗进展期肝细胞癌的预后评价指标尚没有统一的标准。甲胎蛋白作为重要的肝癌肿瘤标志物,已经广泛地应用于肝细胞癌的筛查诊断,并被认为具有潜在的预测肝细胞癌患者的预后价值。本文总结了近几年来关于甲胎蛋白对索拉菲尼治疗进展期肝细胞癌预后评价的相关文献。从总体上看,甲胎蛋白对于索拉菲尼治疗进展期肝细胞癌预后评价作用是值得肯定的,并可以作为传统的基于影像学资料的肝细胞癌预后评价标准的补充,具有广泛的研究前景和应用价值。     

免疫检查点抑制剂治疗肝细胞癌的研究进展

肝癌的发病率及死亡率在全球恶性肿瘤中均位居前列。初诊的肝细胞癌（hepatocellular carcinoma，HCC）患者大多已处于晚期，失去手术根治的机会，全身治疗成为主要的治疗手段。随着免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）的出现，多种ICIs被批准用于晚期HCC患者，ICIs联合抗血管生成药物为主的靶向药物的治疗方案也被证实比ICIs单药效果更佳。但是，无论是单药ICIs还是联合治疗方案，多数患者仍不能从中获益。根据患者治疗的不同目标，通过肿瘤标记物选择不同的治疗方案是目前临床面临的挑战。本文对目前ICIs以及联合不同药物和局部治疗在HCC的临床研究进展、预测疗效和预后的生物标记物以及耐药性相关问题进行综述。      

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review

BACKGROUNDDespite the use of current standard therapy, the prognosis of patients with unresectable hepatocellular carcinoma (HCC) is poor, with median survival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer [BCLC] stage B) and 6–8 mo for advanced HCC (BCLC stage C). Although patients with early-stage HCC are usually suitable for therapies with curative intention, up to 70% of patients experience relapse within 5 years. In the past decade, the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC, the most common type of liver cancer among adults. Nevertheless, no treatment is useful in the adjuvant setting. Since 2007, the multi-kinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC. However, in 2020, the IMbrave150 trial demonstrated that combination therapy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment.AIMTo conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies, which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease. METHODSA comprehensive literature review was conducted using the PubMed, Scopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis.RESULTSIn the atezolizumab/bevacizumab group, an improvement in overall tumor response, reduction of disease progression, and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab. Hypertension and proteinuria were the most common adverse events, and the rates of adverse events were comparable to those with the monotherapy. Of the studies, there were two completed trials and two ongoing trials analyzed using high quality and low bias. A more thorough analysis was only performed on the completed trials.CONCLUSIONTreatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.     

Systemic treatment of advanced hepatocellular carcinoma: From disillusions to new horizons

Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomised trials.     

The possible role of sorafenib as a part of the multimodal treatment for hepatocellular carcinoma

The role of sorafenib is unclear in multimodal treatment for hepatocellular carcinoma (HCC). We analyzed patients who underwent multimodal treatment including surgical operation for advanced HCC after administration of sorafenib. A 79- year-old man underwent extended right hepatectomy for Stage III huge HCC. Three years later, multiple recurrences observed in the liver, and an extrahepatic tumor was diagnosed. Peritoneal seeding was suspected, thus we decided to start a sorafenib administration. After 11 months, new intrahepatic lesions were detected, but extrahepatic tumor was unchanged. We considered the extrahepatic tumor was solitary and resectable, and new lesions in the liver were still treatable, then we attempted a surgical treatment with partial hepatectomy and ablation therapy. The tumor was successfully resected, and residual viable tumors were treated by radiofrequency ablation. The patient remains alive without recurrence at 7 months. We could perform a surgical treatment for another 2 patients with sorafenib treatment. These results suggested that there are cases of advance HCC in which multimodality treatment including surgical treatment can be achieved after sorafenib administration.     

From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now

Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.     

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 for hepatocellular carcinoma (HCC): from bench to bedside

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. For patients with early resectable disease, surgical resection or transplantation is considered a potentially curative modality for hepatocellular carcinoma (HCC); on the other hand, for patients with unresectable or metastatic disease, treatment is essentially palliative and prior to the approval of sorafenib, there was no globally approved systemic treatment for patients presenting with unresectable or metastatic HCC. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit in a large phase III trial. Thus, novel systemic approaches represent a high unmet medical need in advanced HCC. In this review article, we will try to take a journey through the history of systemic therapeutic options for HCC passing through the current standard options and exploring the potential new systemic options for this disease.     

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。      

Targeting fibroblast growth factor receptor signaling in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the primary type of liver cancer, and both the age-adjusted incidence and mortality of HCC have steadily increased in recent years. Advanced HCC is associated with a very poor survival rate. Despite accumulating data regarding the risk factors for HCC, the mechanisms that contribute to HCC tumorigenesis remain poorly understood. Signaling through the fibroblast growth factor (FGF) family is involved in fibrosis and its progression to cirrhosis of the liver, which is a risk factor for the development of HCC. Furthermore, several alterations in FGF/FGF receptor (FGFR) signaling correlate with the outcomes of HCC patients, suggesting that signaling through this family of proteins contributes to the development or progression of HCC tumors. Currently, there are no established systemic treatments for patients with advanced HCC in whom sorafenib treatment has failed or who were unable to tolerate it. Recently, several multikinase inhibitors that target FGFRs have demonstrated some early evidence of antitumor activity in phase I/II trials. Therefore, this review discusses the molecular implications of FGFR-mediated signaling in HCC and summarizes the clinical evidence for novel FGFR-targeted therapies for HCC currently being studied in clinical trials.