Molecularly targeted therapies for hepatocellular carcinoma: sorafenib as a stepping stone

Since sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials, it has changed the treatment paradigm and become the standard first-line treatment for patients with advanced HCC. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance, and thus the survival advantage was modest, even in patients with preserved liver function. Furthermore, there is currently no biomarker for monitoring the response or resistance to sorafenib. Currently, various kinds of molecularly targeted agents have been developed and are being evaluated in clinical trials. There are several steps required to improve the outcome from sorafenib therapy. First, a reliable predictive and prognostic biomarker is urgently needed. Second, a compelling indication of sorafenib treatment for HCC needs more clinical studies and consensus. Third, the actual benefits of sorafenib to patients with advanced liver dysfunction should be clarified and a more effective strategy for targeted therapy needs to be developed, for example, using a combination of targeted agents acting on different pathways or different levels of a key pathway. Finally, sorafenib could be used with other treatment modalities, such as local ablation or transarterial chemoembolization, to synergize efficacy. Based on the successful introduction of sorafenib, future studies should focus on plans to further improve the outcome of HCC patients by overcoming resistance and maximizing the efficacy of molecularly targeted therapy.     

Future treatment option for hepatocellular carcinoma: a focus on brivanib

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is particularly prevalent in the Asia-Pacific region. Guidelines on the treatment of HCC in Japan come from both consensus-based and evidence-based treatment algorithms. However, patients with extensive liver damage and/or more advanced disease (major vascular invasion and/or extrahepatic spread) are currently ineligible for any treatment. Recent knowledge of hepatocarcinogenesis has led to the targeting of new pathways, particularly the angiogenic pathway, with a specific focus on the vascular endothelial growth factor receptor (VEGFR). Apparently the most studied systemic antiangiogenic agent for HCC is sorafenib. An updated version of the aforementioned treatment algorithms recommends sorafenib therapy for advanced HCC patients with Child-Pugh A liver function and extrahepatic spread or major vascular invasion. Moreover, sorafenib is recommended for use in HCC patients who are refractory or intolerant to transarterial chemoembolization (TACE) with well-preserved liver function (Child-Pugh A). However, one of the unresolved issues is anti-VEGF resistance. It is speculated that novel antiangiogenic agents that combine inhibition of other pathways such as fibroblast growth factor receptor signaling in addition to VEGFR signaling might provide a potential mechanism to overcome anti-VEGF resistance in HCC. Brivanib inhibits both VEGF and fibroblast growth factor receptor signaling. To further investigate the benefits of brivanib for advanced HCC, a broad-spectrum, global, phase III development plan, the Brivanib studies in HCC patients at RISK (BRISK) clinical program, has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC, and this agent may provide a novel therapeutic option for the growing population of patients for whom no other treatment choice exists.     

Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update

Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c‐Raf serine/threonine kinase phosphorylation in the mitogen‐activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing elF4E phosphorylation and downregulating Mcl‐1 levels in tumor cells. Third, sorafenib prevents tumor‐associated angiogenesis by inactivating vascular endothelial growth factor receptors (VEGFR‐2 and ‐3) and the platelet‐derived growth factor receptor‐β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.     

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.     

Mechanisms of hepatocellular carcinoma progression

Hepatocellular carcinoma(HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells,immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.     

Sorafenib enhances proteasome inhibitor-induced cell death via inactivation of Akt and stress-activated protein kinases

Background

Advanced hepatocellular carcinoma (HCC) responds poorly to conventional systemic therapies. Therefore, new effective therapy strategies are urgently needed. Molecular targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own and in combination with other drugs. Sorafenib inhibits proliferation and angiogenesis of HCC by suppressing the Raf serine/threonine kinases and the receptor tyrosine kinases. The proteasome inhibitor bortezomib has shown activity in a variety of solid tumors, including HCC. However, the precise anti-proliferative mechanisms of these agents remain unclear.

Methods

We treated human hepatoma cell lines (Huh7 and Hep3B) and immortalized human hepatocyte (OUMS29) with sorafenib and/or proteasome inhibitors, including epoxomicin and acetyl-leucyl-leucyl-norleucinal. Cytotoxic effects were examined by morphometric analyses of apoptosis and necrosis. Apoptosis was also evaluated by Western blotting of keratin18, PARP and caspase3. The activity of Akt and stress-activated protein kinases was examined by Western blotting.

Results

Both sorafenib and proteasome inhibitors induced apoptosis in Huh7 and OUMS29. However, sorafenib attenuated proteasome inhibitor-induced apoptosis. Sorafenib induced necrosis, especially in combination with proteasome inhibitors. Sorafenib induced down-regulation of Akt synergistically in combination with proteasome inhibitors in Huh7. Sorafenib inhibited both the JNK and p38 pathways in a time- and dose-dependent manner. In addition, sorafenib also inhibited proteasome inhibitor-mediated JNK and p38 activation in both Huh7 and OUMS29.

Conclusions

Sorafenib enhances the anti-proliferative effect of proteasome inhibitors in part by inactivating the Akt signaling pathway and modulating stress-activated protein kinases. The combination of these agents could be an ideal molecular targeted therapy for HCC.     

Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar?) was approved in Japan for 'unresectable hepatocellular carcinoma (HCC)', and was the first molecular-targeted agent for use in HCC. 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 now been approved worldwide. Phase III clinical trials of other molecular-targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways. Finally, current status and future perspective will also be discussed.     

Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks

Hepatocellular carcinoma (HCC) is the primary liver malignancy that contributes towards the second most common cause of cancer‐related mortality. The targeted chemotherapeutic agent, sorafenib, is known to show a statistically significant but limited overall survival advantage in advanced HCC. However, the individual patient response towards sorafenib varies drastically, with most experiencing stable disease and few with partial response; complete response is very rare. Progressive disease despite the treatment is also evident in many patients, indicating drug resistance. These varied responses have been linked with the modulation of several intracellular signaling pathways. Notably, the regulation of these pathways through diverse operating biomolecules, including microRNAs (miRNAs), is the focus of recent studies. MicroRNAs are tiny, non‐coding RNA molecules that regulate the expression of several target genes. In addition, miRNAs are known to play a role in the progression of HCC carcinogenesis. Interestingly, miRNAs have also been identified to play differential roles in terms of sorafenib response in HCC such as biomarkers and functional modulation of cellular response to sorafenib, hence, they are also being therapeutically evaluated. This review outlines the role of reported miRNAs in different aspects of sorafenib response in HCC.     

Immune checkpoint blockade for the treatment of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high recurrence rate. Currently, tyrosine kinase inhibitors (TKIs) are the first‐line treatment for cases refractory to conventional therapies. However, the acquisition of somatic mutations can result in TKI resistance. Clinical evidence suggests that acquired immunity contributes to the suppression of tumor recurrence, indicating the potential of induced antitumor immune reaction for the treatment of HCC. Recently, immune checkpoint inhibitors have become available for the treatment of malignancies. They are effective regardless of the response to prior therapies and a durable effect can be expected, which should be attributed to an adaptive immunity to HCC components. The results of phase I/II trials of nivolumab, an anti‐programmed cell death‐1 antibody, showed that 20% of patients showed objective response and that nivolumab was effective regardless of prior sorafenib treatment and viral status. Nivolumab received expedited Food and Drug Administration approval in 2017 for the treatment of advanced HCC after failure or intolerance to sorafenib. However, the majority of the patients remain refractory, likely due to the solid immune suppressive status, which involves many stromal cells, humoral mediators, and suppressive checkpoint molecules. Therefore, current clinical trials are focusing on how immunosuppressive conditions in HCC might be overcome using immune checkpoint inhibitors in combination with different types of immune checkpoint blockades, TKIs, and other conventional treatments. The development of immune checkpoint inhibitors is rapidly progressing and these inhibitors are likely to be key agents for HCC treatment in the near feature.     

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma

BACKGROUNDSorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.AIMTo explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.METHODSThe protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq).RESULTSYB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.CONCLUSIONOverall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.     

Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein

Patients with hepatocellular carcinoma(HCC) accompanying portal vein tumor thrombosis(PVTT) have relatively few therapeutic options and an extremely poor prognosis. These patients are classified into barcelonaclinic liver cancer stage C and sorafenib is suggested as the standard therapy of care. However, overall survival(OS) gain from sorafenib is unsatisfactory and better treatment modalities are urgently required. Therefore, we critically appraised recent data for the various treatment strategies for patients with HCC accompanying PVTT. In suitable patients, even surgical resection can be considered a potentially curative strategy. Transarterial chemoembolization(TACE) can be performed effectively and safely in a carefully chosen population of patients with reserved liver function and sufficient collateral blood flow nearby the blocked portal vein. A recent metaanalysis demonstrated that TACE achieved a substantial improvement of OS in HCC patients accompanying PVTT compared with best supportive care. In addition, transarterial radioembolization(TARE) using yttrium-90 microspheres achieves quality-of-life advantages and is as effective as TACE. A large proportion of HCC patients accompanying PVTT are considered to be proper for TARE. Moreover, TACE or TARE achieved comparable outcomes to sorafenib in recent studies and it was also reported that the combination of radiotherapy with TACE achieved a survival gain compared to sorafenib in HCC patients accompanying PVTT. Surgical resectionbased multimodal treatments, transarterial approaches including TACE and TARE, and TACE-based appropriate combination strategies may improve OS of HCC patients accompanying PVTT.     

Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy

Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.     

Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response

Background

Spontaneous regression of hepatocellular carcinoma (HCC) is well documented, although the aetiology of this phenomenon remains unknown.

Methods

A review of the English literature was performed for reports of spontaneous regression of HCC. Reports were classified by mechanism based on the available information.

Results

Spontaenous regression of HCC has been identified in 75 patients. The most common mechanisms of regression identified were tumour hypoxia (n= 21, 28.0%), a systemic inflammatory response (n= 25, 33.3%) and unknown (n= 29, 38.7%). In patients where tumour hypoxia was described as the aetiology, mechanisms included spontaneous hepatic artery thrombosis and sustained systemic hypotension. In patients where a systemic inflammatory response was the aetiology, mechanisms included cholangitis, trauma and elevated cytokine levels.

Discussion

Spontaneous regression of HCC is most commonly associated with tumour hypoxia or a systemic inflammatory response. Determining the aetiology of spontaneous regression may identify potential therapeutic pathways. Tumour hypoxia is already the basis of treatment modalities such as hepatic artery embolization and the anti-angiogenic agent sorafenib. However, treatment modalities for HCC do not currently include immune-directed therapies; this may prove to be a worthy target for future research.     

Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells

BackgroundSorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib. As the activation of AKT/mTOR played a pivotal role in sorafenib resistance, we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells.MethodsThe sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines. The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method. Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting.ResultsSorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells, which underscores the significance of AKT activation. Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction. Torin2 successfully suppressed the sorafenib-activated mTORC2-AKT axis, leading to the dephosphorylation of Ser136 in BAD protein, and increased the expression of total BAD, which contributed to the apoptosis in sorafenib-resistant HCC cells.ConclusionsIn this study, Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenib-resistant HCC cells, via the suppression of mTORC2-AKT-BAD pathway. Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.     

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.     

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.     

Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: A comprehensive review

The natural history of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is dismal (approximately 2-4 mo), and PVTT is reportedly found in 10%-40% of HCC patients at diagnosis. According to the Barcelona Clinic Liver Cancer (BCLC) Staging System (which is the most widely adopted HCC management guideline), sorafenib is the standard of care for advanced HCC (i.e., BCLC stage C) and the presence of PVTT is included in this category. However, sorafenib treatment only marginally prolongs patient survival and, notably, its therapeutic efficacy is reduced in patients with PVTT. In this context, there have been diverse efforts to develop alternatives to current standard systemic chemotherapies or combination treatment options. To date, many studies on transarterial chemoembolization, 3-dimensional conformal radiotherapy, hepatic arterial chemotherapy, and transarterial radioembolization report better overall survival than sorafenib therapy alone, but their outcomes need to be verified in future prospective, randomized controlled studies in order to be incorporated into current treatment guidelines. Additionally, combination strategies have been applied to treat HCC patients with PVTT, with the hope that the possible synergistic actions among different treatment modalities would provide promising results. This narrative review describes the current status of the management options for HCC with PVTT, with a focus on overall survival.     

非编码RNA在索拉非尼治疗肝细胞癌耐药中的作用机制

索拉非尼作为晚期肝细胞癌的一线治疗药物,能够有效改善肝癌患者预后。但索拉非尼耐药已经成为影响肝细胞癌治疗效果的主要障碍。近年来研究发现,非编码RNA在肝细胞癌索拉非尼耐药中起着关键作用。总结了非编码RNA通过诱导肝癌细胞自噬、促进肝癌干细胞增殖、促进肝癌细胞上皮-间质转化过程、抑制肝癌细胞凋亡以及调节肝癌组织微环境来调节肝癌细胞对索拉非尼的敏感性。指出了非编码RNA调控肝细胞癌索拉非尼耐药的分子机制在克服耐药方面的潜在临床意义。     

Therapeutic Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma Recurrence After Liver Transplantation: A Systematic Review and Meta-Analysis

Background: Hepatocellular carcinoma (HCC) recurrence is still threatening patient survival after liver transplantation (LT). The efficacy and safety of sorafenib in the setting of post-LT recurrence are still equivocal. This study aims to disclose the efficacy and safety profile of sorafenib in treating post-LT HCC recurrence.Materials and Methods: Electronic databases were searched to retrieve relevant publications suitable for inclusion. Data from 23 studies containing 411 patients were analyzed. The primary outcome of interest was 1-year survival rate after sorafenib treatment, and the secondary endpoints included median overall survival (OS), time to progression (TTP), treatment response, and adverse events.Results: Patients with HCC recurrence after LT treated with sorafenib achieved a 1-year survival rate of 56.8%, with a median OS of 12.8 months and a median TTP of 6.0 months. Univariate logistic regression analysis showed that male gender (P = .048), TTP (P = .021), median duration of sorafenib (P = .021), diarrhea (P = .027), fatigue (P = .044), and partial response (P = .026) were associated with a better 1-year survival rate. In addition, sorafenib exerted a significant superior effect on OS compared with best supportive care in the setting of untreatable post-LT HCC recurrence.Conclusions: Based on the results of this meta-analysis, sorafenib therapy seems to be safe and feasible and exhibits survival benefit in patients with post-LT HCC recurrence. However, prospective randomized controlled trials with larger sample sizes and more rigorous study design are required to confirm the efficacy of sorafenib.