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Zhou Y, Li J, Ying J. Anti-PD-1/L1 antibody plus anti-VEGF antibody vs. plus VEGFR-targeted TKI as first-line therapy for unresectable hepatocellular carcinoma: a network meta-analysis. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:568-580. [PMID: 38966165 PMCID: PMC11220314 DOI: 10.37349/etat.2024.00236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/19/2024] [Indexed: 07/06/2024] Open
Abstract
Background This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. Methods After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. Results With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65-1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82-1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54-0.77). Conclusions A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.
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Affiliation(s)
- Yiwen Zhou
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Jingjing Li
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
| | - Jieer Ying
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, Zhejiang, China
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2
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Zhou XQ, Li YP, Dang SS. Precision targeting in hepatocellular carcinoma: Exploring ligand-receptor mediated nanotherapy. World J Hepatol 2024; 16:164-176. [PMID: 38495282 PMCID: PMC10941735 DOI: 10.4254/wjh.v16.i2.164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 02/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.
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Affiliation(s)
- Xia-Qing Zhou
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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Servin F, Collins JA, Heiselman JS, Frederick-Dyer KC, Planz VB, Geevarghese SK, Brown DB, Jarnagin WR, Miga MI. Simulation of Image-Guided Microwave Ablation Therapy Using a Digital Twin Computational Model. IEEE OPEN JOURNAL OF ENGINEERING IN MEDICINE AND BIOLOGY 2023; 5:107-124. [PMID: 38445239 PMCID: PMC10914207 DOI: 10.1109/ojemb.2023.3345733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/14/2023] [Accepted: 12/04/2023] [Indexed: 03/07/2024] Open
Abstract
Emerging computational tools such as healthcare digital twin modeling are enabling the creation of patient-specific surgical planning, including microwave ablation to treat primary and secondary liver cancers. Healthcare digital twins (DTs) are anatomically one-to-one biophysical models constructed from structural, functional, and biomarker-based imaging data to simulate patient-specific therapies and guide clinical decision-making. In microwave ablation (MWA), tissue-specific factors including tissue perfusion, hepatic steatosis, and fibrosis affect therapeutic extent, but current thermal dosing guidelines do not account for these parameters. This study establishes an MR imaging framework to construct three-dimensional biophysical digital twins to predict ablation delivery in livers with 5 levels of fat content in the presence of a tumor. Four microwave antenna placement strategies were considered, and simulated microwave ablations were then performed using 915 MHz and 2450 MHz antennae in Tumor Naïve DTs (control), and Tumor Informed DTs at five grades of steatosis. Across the range of fatty liver steatosis grades, fat content was found to significantly increase ablation volumes by approximately 29-l42% in the Tumor Naïve and 55-60% in the Tumor Informed DTs in 915 MHz and 2450 MHz antenna simulations. The presence of tumor did not significantly affect ablation volumes within the same steatosis grade in 915 MHz simulations, but did significantly increase ablation volumes within mild-, moderate-, and high-fat steatosis grades in 2450 MHz simulations. An analysis of signed distance to agreement for placement strategies suggests that accounting for patient-specific tumor tissue properties significantly impacts ablation forecasting for the preoperative evaluation of ablation zone coverage.
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Affiliation(s)
- Frankangel Servin
- Department of Biomedical EngineeringVanderbilt UniversityNashvilleTN37235USA
- Vanderbilt Institute for Surgery and EngineeringVanderbilt UniversityNashvilleTN37235USA
| | - Jarrod A. Collins
- Department of Biomedical EngineeringVanderbilt UniversityNashvilleTN37235USA
| | - Jon S. Heiselman
- Department of Biomedical EngineeringVanderbilt UniversityNashvilleTN37235USA
- Vanderbilt Institute for Surgery and EngineeringVanderbilt UniversityNashvilleTN37235USA
- Department of Surgery, Hepatopancreatobiliary ServiceMemorial Sloan Kettering Cancer CenterNew YorkNY10065USA
| | | | - Virginia B. Planz
- Department of RadiologyVanderbilt University Medical CenterNashvilleTN37235USA
| | | | - Daniel B. Brown
- Department of RadiologyVanderbilt University Medical CenterNashvilleTN37235USA
| | - William R. Jarnagin
- Department of Surgery, Hepatopancreatobiliary ServiceMemorial Sloan Kettering Cancer CenterNew YorkNY10065USA
| | - Michael I. Miga
- Department of Biomedical EngineeringVanderbilt UniversityNashvilleTN37235USA
- Vanderbilt Institute for Surgery and EngineeringVanderbilt UniversityNashvilleTN37235USA
- Department of RadiologyVanderbilt University Medical CenterNashvilleTN37235USA
- Department of Neurological SurgeryVanderbilt University Medical CenterNashvilleTN37235USA
- Department of OtolaryngologyVanderbilt University Medical CenterNashvilleTN37235USA
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4
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Zhu XF, Sun ZL, Ma J, Hu B, Yu MC, Liu XJ, Yang P, Xu Y, Ju D, Mu Q. Synergistic anticancer effect of flavonoids from Sophora alopecuroides with Sorafenib against hepatocellular carcinoma. Phytother Res 2023; 37:592-610. [PMID: 36180975 DOI: 10.1002/ptr.7637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 08/23/2022] [Accepted: 09/13/2022] [Indexed: 01/30/2023]
Abstract
Sorafenib (SF), a multi-kinase inhibitor, is the first FDA-approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. Sophora alopecuroides L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti-tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A (1), sophoraflavanone G (3), and trifolirhizin (17) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC50 of SF reduced by 5.8-fold, 3.6-fold, and 3.5-fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds 3 or 17 combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial-mediated apoptotic pathway, involving higher Bax/Bcl-2 expressions with the activation of caspase-9 and -3, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co-suppression of ERK and AKT signaling pathways. Furthermore, compound 3 significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid 3 and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.
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Affiliation(s)
- Xiao-Feng Zhu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Zhong-Lin Sun
- School of Pharmacy, Fudan University, Shanghai, China
| | - Jing Ma
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Min-Cheng Yu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Xiu-Jie Liu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Ping Yang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Yang Xu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China
| | - Dianwen Ju
- School of Pharmacy, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of ImmunoTherapeutics, Shanghai, China
| | - Qing Mu
- School of Pharmacy, Fudan University, Shanghai, China
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5
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Li S, Wu J, Wu J, Fu Y, Zeng Z, Li Y, Li H, Liao W, Yan M. Prediction of early treatment response to the combination therapy of TACE plus lenvatinib and anti-PD-1 antibody immunotherapy for unresectable hepatocellular carcinoma: Multicenter retrospective study. Front Immunol 2023; 14:1109771. [PMID: 36875116 PMCID: PMC9981935 DOI: 10.3389/fimmu.2023.1109771] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/01/2023] [Indexed: 02/19/2023] Open
Abstract
Background and aim The purpose of this study was to investigate and validate the efficacy of a nomogram model in predicting early objective response rate (ORR) in u-HCC patients receiving a combination of TACE, Lenvatinib, and anti-PD-1 antibody treatment after 3 months (triple therapy). Method This study included 169 u-HCC cases from five different hospitals. As training cohorts (n = 102), cases from two major centers were used, and external validation cohorts (n = 67) were drawn from the other three centers. The clinical data and contrast-enhanced MRI characteristics of patients were included in this retrospective study. For evaluating MRI treatment responses, the modified revaluation criteria in solid tumors (mRECIST) were used. Univariate and multivariate logistic regression analyses were used to select relevant variables and develop a nomogram model. Our as-constructed nomogram was highly consistent and clinically useful, as confirmed by the calibration curve and decision curve analysis (DCA); an independent external cohort also calibrated the nomogram. Results The ORR was 60.7% and the risk of early ORR was independently predicted by AFP, portal vein tumor thrombus (PVTT), tumor number, and size in both the training (C-index = 0.853) and test (C-index = 0.731) cohorts. The calibration curve revealed that the nomogram-predicted values were consistent with the actual response rates in both cohorts. Furthermore, DCA indicated that our developed nomogram performed well in clinical settings. Conclusion The nomogram model accurately predicts early ORR achieved by triple therapy in u-HCC patients, which aids in individual decision-making and modifying additional therapies for u-HCC cases.
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Affiliation(s)
- Shuqun Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Junyi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Jiayi Wu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yangkai Fu
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhenxin Zeng
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Yinan Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Han Li
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
| | - Weijia Liao
- Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Maolin Yan
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.,Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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7
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Taha AM, Aboulwafa MM, Zedan H, Helmy OM. Ramucirumab combination with sorafenib enhances the inhibitory effect of sorafenib on HepG2 cancer cells. Sci Rep 2022; 12:17889. [PMID: 36284117 PMCID: PMC9596484 DOI: 10.1038/s41598-022-21582-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/29/2022] [Indexed: 01/20/2023] Open
Abstract
Sorafenib, an oral multiple kinase inhibitor, is the standardized treatment for hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. In this study we set out to investigate the effect of combining sorafenib with either bevacizumab (anti-VEGF), panitumumab (anti-EGFR) or ramucirumab (anti-VEGFR2) on HepG2 cancer cell line with the aim of improving efficacy and possibility of therapeutic dose reduction of sorafenib.: HepG2 cancer cell line was treated with sorafenib alone or in combination with either bevacizumab, panitumumab or ramucirumab. Cell proliferation; apoptosis and cell cycle distribution; gene expression of VEGFR2, EGFR, MMP-9 and CASPASE3; the protein levels of pVEGFR2 and pSTAT3 and the protein expression of CASPASE3, EGFR and VEGFR2 were determined. Combined treatments of sorafenib with ramucirumab or panitumumab resulted in a significant decrease in sorafenib IC50. Sorafenib combination with ramucirumab or bevacizumab resulted in a significant arrest in pre-G and G0/G1 cell cycle phases, significantly induced apoptosis and increased the relative expression of CASPASE3 and decreased the anti-proliferative and angiogenesis markers´ MMP-9 and pVEGFR2 or VEGFR2 in HepG2 cells. A significant decrease in the levels of pSTAT3 was only detected in case of sorafenib-ramucirumab combination. The combined treatment of sorafenib with panitumumab induced a significant arrest in pre-G and G2/M cell cycle phases and significantly decreased the relative expression of EGFR and MMP-9. Sorafenib-ramucirumab combination showed enhanced apoptosis, inhibited proliferation and angiogenesis in HepG2 cancer cells. Our findings suggest that ramucirumab can be a useful as an adjunct therapy for improvement of sorafenib efficacy in suppression of HCC.
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Affiliation(s)
| | - Mohammad Mabrouk Aboulwafa
- grid.7269.a0000 0004 0621 1570Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Al Khalifa Al Ma’moun St., Abbassia, Cairo, Egypt ,Present Address: Faculty of Pharmacy, King Salman International University, Ras-Sudr, South Sinai Egypt
| | - Hamdallah Zedan
- grid.7776.10000 0004 0639 9286Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-eini St., Cairo, Egypt
| | - Omneya Mohamed Helmy
- grid.7776.10000 0004 0639 9286Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-eini St., Cairo, Egypt
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Sukowati C, Cabral LKD, Tiribelli C. Immune checkpoint and angiogenic inhibitors for the treatment of hepatocellular carcinoma: It takes two to tangle. Ann Hepatol 2022; 27:100740. [PMID: 35809835 DOI: 10.1016/j.aohep.2022.100740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023]
Abstract
Immunotherapy represents an effective and promising option in various cancers, including in hepatocellular carcinoma (HCC). The immune checkpoint inhibitors (ICIs) have shown a remarkable breakthrough in the last decade, in addition to molecular targeted therapy of angiogenesis such as tyrosine kinases inhibitors. ICIs provide new regimen that can be applied in different stages of the disease. In parallel, HCC progression is related to the tumor microenvironment (TME), involving the cross-talk between various cellular and non-cellular components within the TME niche. It appears logical to synergistically target several HCC components to increase the efficacy of the treatment. In this paper, we summarize evidence that the combination therapy of ICIs and angiogenesis inhibitors would be a potentially better strategy for HCC treatment.
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Affiliation(s)
- Caecilia Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Loraine Kay D Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Doctoral School in Molecular Biomedicine, University of Trieste, Piazzale Europa, 1, Trieste 34127, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Campus Basovizza, SS14 km 163.5, Trieste 34149, Italy
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Xie Y, Yan F, Wang X, Yu L, Yan H, Pu Q, Li W, Yang Z. Mechanisms and network pharmacological analysis of Yangyin Fuzheng Jiedu prescription in the treatment of hepatocellular carcinoma. Cancer Med 2022; 12:3237-3259. [PMID: 36043445 PMCID: PMC9939140 DOI: 10.1002/cam4.5064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/22/2022] [Accepted: 07/03/2022] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE To identify the key drugs of Yangyin Fuzheng Jiedu prescription (YFJP) and investigate their therapeutic effects against hepatocellular carcinoma (HCC) and the potential mechanism using network pharmacology. METHODS The H22 tumor-bearing mouse model was established. Thirty male BALB/c mice were divided randomly into five groups. The mice were orally treated with either disassembled prescriptions of YFJP or saline solution continuously for 14 days. The mice were weighed every 2 days during treatment and the appearance of tumors was observed by photographing. The tumor inhibition rate and the spleen and thymus indexes were calculated. Hematoxylin and eosin and immunohistochemical staining were performed to observe the histological changes and tumor-infiltrating lymphocytes. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. The proportion of CD8+ T cells and the expression of programmed cell death protein 1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (Tim-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were analyzed using flow cytometry. The production of serum cytokines was detected using the Milliplex® MAP mouse high sensitivity T cell panel kit. The active components of the key drugs and HCC-related target proteins were obtained from the corresponding databases. The putative targets for HCC treatment were screened by target mapping, and potential active components were screened by constructing a component-target network. The interactive targets of putative targets were obtained from the STRING database to construct the protein-protein interaction network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed based on potential targets. The gene-gene inner and component-target-pathway networks were constructed and analyzed to screen the key targets. Western blotting was used to evaluate the protein expression of the key targets in the tumor-bearing mouse model. The binding activity of the key targets and compounds was verified by molecular docking. RESULTS Among the three disassembled prescriptions of YFJP, the Fuzheng prescription (FZP) showed significant antitumor effects and inhibited weight loss during the treatment of H22 tumor-bearing mice. FZP increased the immune organ index and the levels of CD8+ and CD3+ T cells in the spleen and peripheral blood of H22 tumor-bearing mice. FZP also reduced the expression of PD-1, TIGIT, and TIM3 in CD8+ T cells and the production of IL-10, IL-4, IL-6, and IL-1β. Network pharmacology and experimental validation showed that the key targets of FZP in the treatment of HCC were PIK3CA, TP53, MAPK1, MAPK3, and EGFR. The therapeutic effect on HCC was evaluated based on HCC-related signaling pathways, including the PIK3-Akt signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. GO enrichment analysis indicated that FZP positively regulated the molecular functions of transferases and kinases on the cell surface through membrane raft, membrane microarea, and other cell components to inhibit cell death and programmed cell death. CONCLUSION FZP was found to be the key disassembled prescription of YFJP that exerted antitumor and immunoregulatory effects against HCC. FZP alleviated T cell exhaustion and improved the immunosuppressive microenvironment via HCC-related targets, pathways, and biological processes.
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Affiliation(s)
- Yuqing Xie
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Fengna Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Xinhui Wang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Lihua Yu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Huiwen Yan
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Qing Pu
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
| | - Weihong Li
- School of Traditional Chinese MedicineBeijing University of Chinese MedicineBeijingP.R. China
| | - Zhiyun Yang
- Center of Integrative Medicine, Beijing Ditan HospitalCapital Medical UniversityBeijingP.R. China
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10
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Gnocchi D, Kurzyk A, Mintrone A, Lentini G, Sabbà C, Mazzocca A. Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma. Biochimie 2022; 202:180-189. [PMID: 35952946 DOI: 10.1016/j.biochi.2022.07.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most threatening tumours in the world today. Pharmacological treatments for HCC mainly rely on protein kinase inhibitors, such as sorafenib and regorafenib. Even so, these approaches exhibit side effects and acquired drug resistance, which is an obstacle to HCC treatment. We have previously shown that selective lysophosphatidic acid receptor 6 (LPAR6) chemical antagonists inhibit HCC growth. Here, we investigated whether LPAR6 mediates resistance to sorafenib by affecting energy metabolism in HCC. To uncover the role of LPAR6 in drug resistance and cancer energy metabolism, we used a gain-of-function and loss-of-function approach in 2D tissue and 3D spheroids. LPAR6 was ectopically expressed in HLE cells (HLE-LPAR6) and knocked down in HepG2 (HepG2 LPAR6-shRNA). Measurements of oxygen consumption and lactate and pyruvate production were performed to assess the energy metabolism response of HCC cells to sorafenib treatment. We found that LPAR6 mediates the resistance of HCC cells to sorafenib by promoting lactic acid fermentation at the expense of oxidative phosphorylation (OXPHOS) and that the selective LPAR6 antagonist 9-xanthenyl acetate (XAA) can effectively overcome this resistance. Our study shows for the first time that an LPAR6-mediated metabolic mechanism supports sorafenib resistance in HCC and proposes a pharmacological approach to overcome it.
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Affiliation(s)
- Davide Gnocchi
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Agata Kurzyk
- Department of Cancer Biology, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland
| | - Antonella Mintrone
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Giovanni Lentini
- Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, via Orabona, 4 - 70125, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Piazza G. Cesare, 11 - 70124, Bari, Italy.
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11
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Zhang Z, Li C, Liao W, Huang Y, Wang Z. A Combination of Sorafenib, an Immune Checkpoint Inhibitor, TACE and Stereotactic Body Radiation Therapy versus Sorafenib and TACE in Advanced Hepatocellular Carcinoma Accompanied by Portal Vein Tumor Thrombus. Cancers (Basel) 2022; 14:cancers14153619. [PMID: 35892878 PMCID: PMC9332229 DOI: 10.3390/cancers14153619] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
Background: This study compared the effectiveness of the combined administration of sorafenib, an immune checkpoint inhibitor, transcatheter arterial chemoembolization (TACE), and stereotactic body radiation therapy (SBRT) (SITS group) vs. sorafenib combined with TACE (ST group) in treating and downstaging advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods: The present study included patients with advanced HCC and PVTT treated with one of the above combination therapies. The downstaging rate, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) were assessed. Results: Sixty-two patients were analyzed. The ORR was elevated in the SITS group compared with the ST group (p = 0.036), but no differences were found in DCR (p = 0.067). The survival analysis revealed higher PFS (p = 0.015) and OS (p = 0.013) in the SITS group, with median PFS and OS times of 10.4 and 13.8 months, respectively. Ten patients displayed successful downstaging and underwent surgery in the SITS group, vs. none in the ST group. The prognosis was better in surgically treated patients compared with the non-surgery subgroup, based on PFS (p < 0.001) and OS (p = 0.003). Despite a markedly higher rate of AEs in the SITS group (p = 0.020), including two severe AEs, the SITS combination therapy had an acceptable safety profile. Conclusion: The SITS combination therapy yields higher PFS and OS than the combined administration of sorafenib and TACE in patients with advanced HCC and PVTT, especially as a downstaging strategy before surgery.
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Affiliation(s)
- Zeyu Zhang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410078, China; (Z.Z.); (W.L.); (Z.W.)
| | - Chan Li
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410078, China;
| | - Weijun Liao
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410078, China; (Z.Z.); (W.L.); (Z.W.)
| | - Yun Huang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410078, China; (Z.Z.); (W.L.); (Z.W.)
- Correspondence: ; Tel.: +86-137-8710-2228
| | - Zhiming Wang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410078, China; (Z.Z.); (W.L.); (Z.W.)
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12
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Inhibition of Metastatic Hepatocarcinoma by Combined Chemotherapy with Silencing VEGF/VEGFR2 Genes through a GalNAc-Modified Integrated Therapeutic System. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27072082. [PMID: 35408480 PMCID: PMC9000533 DOI: 10.3390/molecules27072082] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor related to high mortality and is still lacking a satisfactory cure. Tumor metastasis is currently a major challenge of cancer treatment, which is highly related to angiogenesis. The vascular endothelial growth factor (VEGF)/VEGFR signaling pathway is thus becoming an attractive therapeutic target. Moreover, chemotherapy combined with gene therapy shows great synergistic potential in cancer treatment with the promise of nanomaterials. In this work, a formulation containing 5-FU and siRNA against the VEGF/VEGFR signaling pathway into N-acetyl-galactosamine (GalNAc)-modified nanocarriers is established. The targeting ability, biocompatibility and pH-responsive degradation capacity ensure the efficient transport of therapeutics by the formulation of 5-FU/siRNA@GalNAc-pDMA to HCC cells. The nano-construct integrated with gene/chemotherapy exhibits significant anti-metastatic HCC activity against C5WN1 liver cancer cells with tumorigenicity and pulmonary metastasis in the C5WN1-induced tumor-bearing mouse model with a tumor inhibition rate of 96%, which is promising for future metastatic HCC treatment.
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13
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Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
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Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
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14
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Zheng P, Huang Z, Tong DC, Zhou Q, Tian S, Chen BW, Ning DM, Guo YM, Zhu WH, Long Y, Xiao W, Deng Z, Lei YC, Tian XF. Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways. World J Gastrointest Oncol 2022; 14:450-477. [PMID: 35317323 PMCID: PMC8919004 DOI: 10.4251/wjgo.v14.i2.450] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/19/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined.
AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.
METHODS In the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo, SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.
RESULTS The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways.
CONCLUSION In summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.
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Affiliation(s)
- Piao Zheng
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Zhen Huang
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Dong-Chang Tong
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Qing Zhou
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Sha Tian
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Bo-Wei Chen
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Di-Min Ning
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yin-Mei Guo
- Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Wen-Hao Zhu
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yan Long
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
| | - Wei Xiao
- Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Zhe Deng
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yi-Chen Lei
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xue-Fei Tian
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
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15
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Yen CC, Yen CJ. Safety of ramucirumab treatment in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein. Expert Opin Drug Saf 2022; 21:157-166. [PMID: 34668832 DOI: 10.1080/14740338.2022.1995353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 10/15/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the second most common cause of cancer-induced deaths worldwide, and limited therapeutic options are available for patients with advanced disease. Ramucirumab, a monoclonal antibody that blocks the vascular endothelial growth factor (VEGF) receptor-2, is the first biomarker-selected systemic agent with therapeutic efficacy, tolerability, and favorable patient-reported outcomes in patients with advanced HCC and elevated serum α-fetoprotein levels ≥400 ng/mL, who are resistant or intolerant to sorafenib therapy. However, treatment-induced adverse events (AEs), such as hypertension, proteinuria, bleeding, thromboembolism, and gastrointestinal perforation remain challenging and potentially fatal concerns. AREAS COVERED This review discusses the published or ongoing studies and subgroup analyses on ramucirumab therapy in patients with advanced HCC. We present information on the risks of ramucirumab-induced common or rare AEs and their management. EXPERT OPINION Ramucirumab toxicity secondary to VEGF inhibition is similar to the AEs that are known to be associated with other VEGF-blocking antibodies. Common AEs can be safely treated using conventional measures; however, rare and potentially fatal AEs necessitate close monitoring. With regard to the safety profile, more promising ramucirumab-containing combination therapies are likely to pave the future path for effective HCC treatment.
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Affiliation(s)
- Chih-Chieh Yen
- Division of Hematology/ Oncology, Department of Internal Medicine, National Cheng Kung University Hospital Douliou Branch, Yunlin, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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16
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Wei J, Liu R, Zhang J, Liu S, Yan D, Wen X, Tian X. Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption. Front Pharmacol 2021; 12:761763. [PMID: 34819863 PMCID: PMC8606670 DOI: 10.3389/fphar.2021.761763] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/04/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses. Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model. Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model. Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.
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Affiliation(s)
- Jingyao Wei
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ruijuan Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jiali Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Shuaibing Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Dan Yan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xueqian Wen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xin Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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17
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Mohr R, Tacke F. Therapie des hepatozellulären Karzinoms – eine neue Dekade? Drug Res (Stuttg) 2021; 71:S22-S23. [PMID: 34788884 DOI: 10.1055/a-1606-5955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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18
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Philips CA, Rajesh S, Nair DC, Ahamed R, Abduljaleel JK, Augustine P. Hepatocellular Carcinoma in 2021: An Exhaustive Update. Cureus 2021; 13:e19274. [PMID: 34754704 PMCID: PMC8569837 DOI: 10.7759/cureus.19274] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2021] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer is a challenging global health concern with an estimated more than a million persons to be affected annually by the year 2025. The commonest type is hepatocellular carcinoma (HCC), which has been increasing in incidence the world over, mostly due to chronic viral hepatitis B infection. In the last decade, paradigm changes in the etiology, understanding of molecular biology, and pathogenesis, including the role of gut microbiota; medical and surgical treatments, and outcome trends are notable. The application of omics-based technology has helped us unlock the molecular and immune landscape of HCC, through which novel targets for drug treatment such as immune-checkpoint inhibitors have been identified. Novel tools for the surveillance and diagnosis of HCC include protein-, genomics-, and composite algorithm-based clinical/biomarker panels. Magnetic resonance imaging-based novel techniques have improved HCC diagnosis through ancillary features that enhance classical criteria while positron emission tomography has shown value in prognostication. Identification of the role of gut microbiota in the causation and progression of HCC has opened areas for novel therapeutic research. A select group of patients still benefit from modified surgical and early interventional radiology treatments. Improvements in radiotherapy protocols, identification of parameters of futility among radiological interventions, and the emergence of novel first-line systemic therapies that include a combination of antiangiogenic and immune-checkpoint inhibitors have seen a paradigm change in progression-free and overall survival. The current review is aimed at providing exhaustive updates on the etiology, molecular biology, biomarker diagnosis, imaging, and recommended treatment options in patients with HCC.
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Affiliation(s)
- Cyriac A Philips
- Clinical and Translational Hepatology, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
| | - Sasidharan Rajesh
- Interventional Hepatobiliary Radiology, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
| | - Dinu C Nair
- Interventional Hepatobiliary Radiology, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
| | - Rizwan Ahamed
- Gastroenterology and Advanced Gastrointestinal (GI) Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
| | - Jinsha K Abduljaleel
- Gastroenterology and Advanced Gastrointestinal (GI) Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
| | - Philip Augustine
- Gastroenterology and Advanced Gastrointestinal (GI) Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, IND
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19
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Deng M, Fang L, Li SH, Zhao RC, Mei J, Zou JW, Wei W, Guo RP. Expression pattern and prognostic value of N6-methyladenosine RNA methylation key regulators in hepatocellular carcinoma. Mutagenesis 2021; 36:369-379. [PMID: 34467992 PMCID: PMC8493108 DOI: 10.1093/mutage/geab032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/01/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is still one of the most common malignancies worldwide. The accuracy of biomarkers for predicting the prognosis of HCC and the therapeutic effect is not satisfactory. N6-methyladenosine (m6A) methylation regulators play a crucial role in various tumours. Our research aims further to determine the predictive value of m6A methylation regulators and establish a prognostic model for HCC. In this study, the data of HCC from The Cancer Genome Atlas (TCGA) database was obtained, and the expression level of 15 genes and survival was examined. Then we identified two clusters of HCC with different clinical factors, constructed prognostic markers and analysed gene set enrichment, proteins’ interaction and gene co-expression. Three subgroups by consensus clustering according to the expression of the 13 genes were identified. The risk score generated by five genes divided HCC patients into high-risk and low-risk groups. In addition, we developed a prognostic marker that can identify high-risk HCC. Finally, a novel prognostic nomogram was developed to accurately predict HCC patients’ prognosis. The expression levels of 13 m6A RNA methylation regulators were significantly upregulated in HCC samples. The prognosis of cluster 1 and cluster 3 was worse. Patients in the high-risk group show a poor prognosis. Moreover, the risk score was an independent prognostic factor for HCC patients. In conclusion, we reveal the critical role of m6A RNA methylation modification in HCC and develop a predictive model based on the m6A RNA methylation regulators, which can accurately predict HCC patients’ prognosis and provide meaningful guidance for clinical treatment.
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Affiliation(s)
- Min Deng
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lin Fang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shao-Hua Li
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rong-Ce Zhao
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jie Mei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing-Wen Zou
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wei Wei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rong-Ping Guo
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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20
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Deng M, Li S, Mei J, Lin W, Zou J, Wei W, Guo R. High SGO2 Expression Predicts Poor Overall Survival: A Potential Therapeutic Target for Hepatocellular Carcinoma. Genes (Basel) 2021; 12:genes12060876. [PMID: 34200261 PMCID: PMC8226836 DOI: 10.3390/genes12060876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/29/2021] [Accepted: 06/03/2021] [Indexed: 02/08/2023] Open
Abstract
Shugoshin2 (SGO2) may participate in the occurrence and development of tumors by regulating abnormal cell cycle division, but its prognostic value in hepatocellular carcinoma (HCC) remains unclear. In this study, we accessed The Cancer Genome Atlas (TCGA) database to get the clinical data and gene expression profile of HCC. The expression of SGO2 in HCC tissues and nontumor tissues and the relationship between SGO2 expression, survival, and clinicopathological parameters were analyzed. The SGO2 expression level was significantly higher in HCC tissues than in nontumor tissues (p < 0.001). An analysis from the Oncomine and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases also demonstrated that SGO2 was upregulated in HCC (all p < 0.001). A logistic regression analysis revealed that the high expression of SGO2 was significantly correlated with gender, tumor grade, pathological stage, T classification, and Eastern Cancer Oncology Group (ECOG) score (all p < 0.05). The overall survival (OS) of HCC patients with higher SGO2 expression was significantly poor (p < 0.001). A multivariate analysis showed that age and high expression of SGO2 were independent predictors of poor overall survival (all p < 0.05). Twelve signaling pathways were significantly enriched in samples with the high-SGO2 expression phenotype. Ten proteins and 34 genes were significantly correlated with SGO2. In conclusion, the expression of SGO2 is closely related to the survival of HCC. It may be used as a potential therapeutic target and prognostic marker of HCC.
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Affiliation(s)
- Min Deng
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shaohua Li
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jie Mei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenping Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jingwen Zou
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wei Wei
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Rongping Guo
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (M.D.); (S.L.); (J.M.); (W.L.); (J.Z.); (W.W.)
- State Key Laboratory of Oncology in South China, Guangzhou 510060, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Correspondence: ; Tel.: +86-188-1980-9988
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21
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Gnocchi D, Castellaneta F, Cesari G, Fiore G, Sabbà C, Mazzocca A. Treatment of liver cancer cells with ethyl acetate extract of Crithmum maritimum permits reducing sorafenib dose and toxicity maintaining its efficacy. J Pharm Pharmacol 2021; 73:1369-1376. [PMID: 34014301 DOI: 10.1093/jpp/rgab070] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC) is one of the most frequent tumours worldwide and available drugs are inadequate for therapeutic results and tolerability. Hence, novel effective therapeutic tools with fewer side effects are of paramount importance. We have previously shown that Crithmum maritimum ethyl acetate extract exerts a cytostatic effect in HCC cells. Here, we tested whether C. maritimum ethyl acetate extract in combination with half sorafenib IC50 dose ameliorated efficacy and toxicity of sorafenib in inhibiting liver cancer cell growth. Moreover, we investigated the mechanisms involved. METHODS Two HCC cell lines (Huh7 and HepG2) were treated with C. maritimum ethyl acetate extract and half IC50 sorafenib dose usually employed in vitro. Then, cell proliferation, growth kinetics and cell toxicity were analysed together with an investigation of the cellular mechanisms involved, focusing on cell cycle regulation and apoptosis. KEY FINDINGS Results show that combined treatment with C. maritimum ethyl acetate extract and half IC50 sorafenib dose decreased cell proliferation comparably to full-dose sorafenib without increasing cell toxicity as confirmed by the effect on cell cycle regulation and apoptosis. CONCLUSIONS These results provide scientific support for the possibility of an effective integrative therapeutic approach for HCC with fewer side effects on patients.
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Affiliation(s)
- Davide Gnocchi
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Francesca Castellaneta
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Gianluigi Cesari
- International Centre for Advanced Mediterranean Agronomic Studies - CHIEAM, Valenzano (BA), Italy
| | - Giorgio Fiore
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Carlo Sabbà
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
| | - Antonio Mazzocca
- Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy
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22
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Lurje I, Werner W, Mohr R, Roderburg C, Tacke F, Hammerich L. In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma. Front Immunol 2021; 12:650486. [PMID: 34025657 PMCID: PMC8137829 DOI: 10.3389/fimmu.2021.650486] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/22/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is a highly prevalent malignancy that develops in patients with chronic liver diseases and dysregulated systemic and hepatic immunity. The tumor microenvironment (TME) contains tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) and is central to mediating immune evasion and resistance to therapy. The interplay between these cells types often leads to insufficient antigen presentation, preventing effective anti-tumor immune responses. In situ vaccines harness the tumor as the source of antigens and implement sequential immunomodulation to generate systemic and lasting antitumor immunity. Thus, in situ vaccines hold the promise to induce a switch from an immunosuppressive environment where HCC cells evade antigen presentation and suppress T cell responses towards an immunostimulatory environment enriched for activated cytotoxic cells. Pivotal steps of in situ vaccination include the induction of immunogenic cell death of tumor cells, a recruitment of antigen-presenting cells with a focus on dendritic cells, their loading and maturation and a subsequent cross-priming of CD8+ T cells to ensure cytotoxic activity against tumor cells. Several in situ vaccine approaches have been suggested, with vaccine regimens including oncolytic viruses, Flt3L, GM-CSF and TLR agonists. Moreover, combinations with checkpoint inhibitors have been suggested in HCC and other tumor entities. This review will give an overview of various in situ vaccine strategies for HCC, highlighting the potentials and pitfalls of in situ vaccines to treat liver cancer.
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Affiliation(s)
- Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Wiebke Werner
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
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23
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Gallage S, García-Beccaria M, Szydlowska M, Rahbari M, Mohr R, Tacke F, Heikenwalder M. The therapeutic landscape of hepatocellular carcinoma. MED 2021; 2:505-552. [PMID: 35590232 DOI: 10.1016/j.medj.2021.03.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/23/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
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24
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Li X, Wang Y, Ye X, Liang P. Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development. Front Mol Biosci 2021; 8:635243. [PMID: 33928118 PMCID: PMC8076864 DOI: 10.3389/fmolb.2021.635243] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the application of antiviral drugs and improved surveillance tools, the number of patients diagnosed with hepatocellular carcinoma (HCC) at an advanced stage and with a dismal prognosis is still on the rise. Systemic treatment with multiple multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib, has been a widely utilized approach for a decade. In addition, the use of a combination of TKIs with other types of compounds, including immune checkpoint inhibitors (ICIs) and antiangiogenic inhibitors, has shown efficacy in treating advanced HCC. However, the presence of intolerable adverse events, low disease response and control rates, and relative short overall survival of such combinatory therapies makes novel or optimized therapies for advance HCC urgently needed. Locoregional therapy (transarterial chemoembolization, and thermal ablation) can destroy primary tumors and decrease tumor burden and is widely used for HCC management. This type of treatment modality can result in local hypoxia and increased vascular permeability, inducing immunogenic effects by releasing tumor antigens from dying cancer cells and producing damage-associated molecular patterns that facilitate antiangiogenic therapy and antitumor immunity. The combination of systemic and locoregional therapies may further produce synergistic effects without overlapping toxicity that can improve prognoses for advanced HCC. In preliminary studies, several combinations of therapeutic modes exhibited promising levels of safety, feasibility, and antitumor effects in a clinical setting and have, thus, garnered much attention. This review aims to provide a comprehensive, up-to-date overview of the underlying mechanisms of combined systemic and locoregional therapies in the treatment of advanced HCC, commenting on both their current status and future direction.
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Affiliation(s)
- Xin Li
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
| | - Yaxi Wang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
- Department of Ultrasound, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xin Ye
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China
| | - Ping Liang
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
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25
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Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy. J Clin Med 2021; 10:jcm10071361. [PMID: 33806224 PMCID: PMC8036296 DOI: 10.3390/jcm10071361] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/20/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. METHODS We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. RESULTS While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (-3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<-6.18 mm2/cm) or a strongly decreasing ∆MMA (<-0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below -6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). CONCLUSION Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.
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Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.
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Affiliation(s)
- Tarik Demir
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
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27
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Shen X, Hu B, Xu J, Qin W, Fu Y, Wang S, Dong Q, Qin L. The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics. Cancer Biol Med 2020; 17:937-952. [PMID: 33299645 PMCID: PMC7721089 DOI: 10.20892/j.issn.2095-3941.2020.0402] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Epigenetic aberration plays an important role in the development and progression of hepatocellular carcinoma (HCC). However, the alteration of RNA N6-methyladenosine (m6A) modifications and its role in HCC progression remain unclear. We therefore aimed to provide evidence using bioinformatics analysis. METHODS We comprehensively analyzed the m6A regulator modification patterns of 605 HCC samples and correlated them with metabolic alteration characteristics. We elucidated 390 gene-based m6A-related signatures and defined an m6Ascore to quantify m6A modifications. We then assessed their values for predicting prognoses and therapeutic responses in HCC patients. RESULTS We identified 3 distinct m6A modification patterns in HCC, and each pattern had distinct metabolic characteristics. The evaluation of m6A modification patterns using m6Ascores could predict the prognoses, tumor stages, and responses to sorafenib treatments of HCC patients. A nomogram based on m6Ascores showed high accuracy in predicting the overall survival of patients. The area under the receiver operating characteristic curve of predictions of 1, 3, and 5-year overall survivals were 0.71, 0.69, and 0.70 in the training cohort, and in the test cohort it was 0.74, 0.75, and 0.71, respectively. M6Acluster C1, which corresponded to hypoactive mRNA methylation, lower expression of m6A regulators, and a lower m6Ascore, was characterized by metabolic hyperactivity, lower tumor stage, better prognosis, and lower response to sorafenib treatment. In contrast, m6Acluster C3 was distinct in its hyperactive mRNA methylations, higher expression of m6A regulators, and higher m6Ascores, and was characterized by hypoactive metabolism, advanced tumor stage, poorer prognosis, and a better response to sorafenib. The m6Acluster, C2, was intermediate between C1 and C3. CONCLUSIONS HCCs harbored distinct m6A regulator modification patterns that contributed to the metabolic heterogeneity and diversity of HCC. Development of m6A gene signatures and the m6Ascore provides a more comprehensive understanding of m6A modifications in HCC, and helps predict the prognosis and treatment response.
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Affiliation(s)
- Xiaotian Shen
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Beiyuan Hu
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jing Xu
- Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Wei Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai 250040, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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28
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Lurje I, Hammerich L, Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J Mol Sci 2020; 21:ijms21197378. [PMID: 33036244 PMCID: PMC7583774 DOI: 10.3390/ijms21197378] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.
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29
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Ivanyi P, Eggers H, Hornig M, Kasper B, Heissner K, Kopp HG, Kirstein M, Ganser A, Grünwald V. Hepatic toxicity during regorafenib treatment in patients with metastatic gastrointestinal stromal tumors. Mol Clin Oncol 2020; 13:72. [PMID: 33005406 DOI: 10.3892/mco.2020.2143] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a multi-target tyrosine kinase inhibitor that has been approved for the treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors (GIST). Severe hepatobiliary toxicity has been reported in patients with colorectal cancer treated with regorafenib, but not in those with GIST. Therefore, the aim of the present study was to investigate the incidence and clinical course of regorafenib-associated hepatic toxicity (HT) in patients with GIST in a real-world setting. Patients with metastatic GIST treated with regorafenib between September 2012 and May 2014 at three German tertiary care centers were followed up until August 2017. Patient records were retrospectively analyzed and descriptive statistics were employed. HT was defined as alterations in the serum values of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase and bilirubin (according to the Common Terminology Criteria for Adverse Events, version 4.0), and/or corresponding clinical signs. The time to clinical progression and the overall survival were calculated by Kaplan-Meier curves. Overall, 21 patients were treated with regorafenib and 5 (23.5%) of those heavily pretreated patients suffered from severe HT during regorafenib treatment. In 4 (80%) of these cases, regorafenib treatment was continued, optimizing individual treatment benefit. Clinical monitoring and adequate therapy management are crucial for ensuring continuation of regorafenib treatment in order to achieve an optimal clinical outcome.
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Affiliation(s)
- Philipp Ivanyi
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
| | - Hendrik Eggers
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
| | - Mareike Hornig
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
| | - Bernd Kasper
- Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, University of Heidelberg, D-68167 Mannheim, Germany
| | - Klaus Heissner
- Department of Oncology, Hematology, Clinical Immunology, Rheumatology and Pneumology, University Hospital and Faculty of Medicine Tübingen, D-72076 Tübingen, Germany
| | - Hans-Georg Kopp
- Department of Oncology, Hematology, Clinical Immunology, Rheumatology and Pneumology, University Hospital and Faculty of Medicine Tübingen, D-72076 Tübingen, Germany
| | - Martha Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, D-30625 Hannover, Germany.,First Department of Medicine-Internal Medicine, University Medical Center Schleswig-Holstein, D-23538 Lübeck, Germany
| | - Arnold Ganser
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
| | - Viktor Grünwald
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany.,Department of Interdisciplinary GU Oncology, West-German Cancer Center Essen, University Hospital Essen, D-45147 Essen, Germany
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