Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma

Yarchoan, Mark; Agarwal, Parul; Villanueva, Augusto; Rao, Shuyun; Dawson, Laura A.; Llovet, Josep M.; Finn, Richard S.; Groopman, John D.; El–Serag, Hashem B.; Monga, Satdarshan P.; Wang, Xin Wei; Karin, Michael; Schwartz, Robert E.; Tanabe, Kenneth K.; Roberts, Lewis R.; Gunaratne, Preethi H.; Tsung, Allan; Brown, Kimberly; Lawrence, Theodore S.; Salem, Riad; Singal, Amit G.; Kim, Amy K.; Rabiee, Atoosa; Resar, Linda S.; Hoshida, Yujin; He, Aiwu Ruth; Ghoshal, Kalpana; Ryan, Patrick B.; Jaffee, Elizabeth M.; Guha, Chandan; Mishra, Lopa; Coleman, C. Norman; Ahmed, Mansoor M.

doi:10.1158/0008-5472.can-19-0803

Cited by 119 publications

(85 citation statements)

References 20 publications

(17 reference statements)

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“…In summary, we find that both virally infected and uninfected HCC respond similarly to inhibitors of the PD-1/ PD-L1 axis. Multiple completed studies of PD-1/PD-L1 therapy alone or in combination with other agents will likely be reported in the next few years, 3 which will further clarify the relationship between HCC etiology and clinical response to these agents. However, our results suggest that viral status should not be used clinically to identify patients for treatment with PD-1/PD-L1 inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Despite clearly having activity in HCC, recent phase 3 studies of PD-1 inhibitors have failed to meet their primary endpoints, highlighting a need for novel biomarkers to identify the subsets of HCC that are most likely to respond to these therapies. 3 HCC usually emerges in the setting of liver cirrhosis of any cause. In one analysis, hepatitis B virus (HBV) or hepatitis C virus (HCV) is responsible for approximately 76% of the global burden of HCC, whereas approximately 24% of HCC worldwide is not virus-associated.…”

Section: Introductionmentioning

confidence: 99%

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Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Danilova

Lim

et al. 2020

J Immunother Cancer

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Background and aimsImmune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear.MethodsWe conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)).ResultsMeta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=−1.4%, 95% CI: −13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC.ConclusionThere is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Danilova

Lim

et al. 2020

J Immunother Cancer

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“… 1 The prognosis of HCC remains poor, with a 5-year survival rate of just 18%, highlighting the limitations of available treatments. 3 When detected early, HCCs are amenable to locoregional therapies and surgery, however the recurrence rate 5-years post-resection is about 70%. 1 Systemic therapies are used for patients diagnosed at more advanced stages.…”

Section: Introductionmentioning

confidence: 99%

“…HCC is very resistant to conventional chemotherapies, 4 but targeted agents such as the multikinase inhibitors sorafenib, lenvatinib, regorafenib and cabozantinib, as well as monoclonal antibodies like ramucirumab (which targets vascular endothelial growth factor [VEGF] receptor 2), confer some survival benefit. 1 , 3 , 5 , 6 Immunotherapy is also being actively tested in HCC, and immune checkpoint inhibitors (ICIs), which are antibodies that block the programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, have shown clinical activity. 3 , 5 , 7 Moreover, a recent study showed very promising effects in patients with unresectable HCC that were treated with antibodies targeting PD-L1 and VEGF.…”

Section: Introductionmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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“…previously, many progresses have been made in understanding the epidemiology, risk factors and molecular profiles of HCC [11]. However, incidence and HCC-specific mortality still continue to increase [12][13][14]. Although some progress has been made in molecular targeted therapy for HCC, the results are still unsatisfactory [15].…”

Section: Discussionmentioning

confidence: 99%

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

Guo

Zhang

et al. 2019

Preprint

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Background Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research aims to mine the Hypoxic related genes (HRGs) on the role of clinical prognosis in HCC. Moreover, we construct and define a model of prognostic predictor (PP) to estimate and improve prognosis of HCC patients.Results 37 differentially expressed HRGs were obtained. It contained 28 up-regulated and 9 down-regulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer and 2 genes were protective factors. The PP was composed of the 10 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, PGK1, ERO1A, LDHA, ENO2, TPI1), and significantly divided patients of HCC into high- and low-risk groups according to overall survival (OS) ( P <0.001). We got the Area Under Curve(AUC) value of risk score calculated by PP was 0.777, which much bigger than other clinical parameters. Besides, PP was verified as an independent prognosis-related parameter (in univariate analyse, HR=1.484, 95% CI=1.342–1.642, P<0.001; in multivariate analyse, HR=1.414, 95% CI=1.258–1.588, P <0.001). Finally, the application of PP in clinic was concluded that the higher the patient's risk score, the higher the corresponding tumor stage and T stage, and the patient's prognosis was poor.Conclusions This study provides hypoxic related molecular targets for the therapeutic intervention. In addition, an individualized prognostic predictor was constructed to predict prognosis for HCC patients .

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Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma

Cited by 119 publications

References 20 publications

Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

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