1
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Zabihi A. The role of biological macromolecules in the regulation of angiogenesis in glioblastoma: Focus on vascular growth factors, integrins, and extracellular matrix proteins. Int J Biol Macromol 2025; 311:143838. [PMID: 40319984 DOI: 10.1016/j.ijbiomac.2025.143838] [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: 02/20/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Glioblastoma, classified as a grade 4 brain tumor, accounts for approximately half of all malignant central nervous system cancers. Despite extensive research and aggressive treatment modalities, much about this disease remains elusive. The proliferation of blood vessels within glioblastoma tumors significantly contributes to their invasive nature, primarily due to the influence of vascular endothelial growth factor-A (VEGF-A). As a result, the past decade has seen a concentrated effort to explore angiogenesis, especially the VEGF signaling pathway, as a therapeutic target for glioblastoma. This investigation led to the FDA approval of bevacizumab, a monoclonal antibody against VEGF-A, for the treatment of recurrent glioblastoma. However, despite promising clinical trials and theoretical research, bevacizumab has not significantly improved patient survival rates. Furthermore, other anti-angiogenic agents targeting the VEGF signaling pathway have shown limited efficacy. This suggests the existence of multiple alternative angiogenic pathways that facilitate vascularization, even when VEGF signaling is inhibited. In this study, we aim to assess the current landscape of anti-angiogenic agents, explore potential resistance mechanisms to such therapies, and suggest strategies to improve the effectiveness of these therapeutic interventions. Our goal is to provide a comprehensive understanding of the limitations of current treatments and to identify new avenues for enhancing therapeutic outcomes in glioblastoma patients.
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Affiliation(s)
- Abbas Zabihi
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University Rasht Branch, Rasht, Iran.
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2
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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [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: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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3
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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4
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Banjan B, Vishwakarma R, Ramakrishnan K, Dev RR, Kalath H, Kumar P, Soman S, Raju R, Revikumar A, Rehman N, Abhinand CS. Targeting AFP-RARβ complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma. Mol Divers 2025; 29:1337-1352. [PMID: 38955977 DOI: 10.1007/s11030-024-10915-8] [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: 03/21/2024] [Accepted: 06/09/2024] [Indexed: 07/04/2024]
Abstract
Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARβ interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARβ complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARβ complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.
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Affiliation(s)
- Bhavya Banjan
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Riya Vishwakarma
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Krishnapriya Ramakrishnan
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Radul R Dev
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Haritha Kalath
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Pankaj Kumar
- Nitte (Deemed to Be University), Department of Pharmaceutical Chemistry, NGSMPS, NGSM Institute of Pharmaceutical Sciences, Mangalore, 575018, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to Be University), Deralakatte, Mangalore, 575018, Karnataka, India
| | - Amjesh Revikumar
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India
- Kerala Genome Data Centre, Kerala Development and Innovation Strategic Council, Vazhuthacaud, Thiruvananthapuram, Kerala, 695014, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, 575018, India.
| | - Chandran S Abhinand
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to Be University), Deralakatte, Mangalore, 575018, Karnataka, India.
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5
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Sun R, Wu C, Gou Y, Zhao Y, Huang P. Advancements in second-line treatment research for hepatocellular carcinoma. Clin Transl Oncol 2025; 27:837-857. [PMID: 39162977 DOI: 10.1007/s12094-024-03653-8] [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: 05/08/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.
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Affiliation(s)
- Ruirui Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Chenrui Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yang Gou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yaowu Zhao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China.
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6
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Chan LL, Kwong TT, Yau JCW, Chan SL. Treatment for hepatocellular carcinoma after immunotherapy. Ann Hepatol 2025; 30:101781. [PMID: 39929474 DOI: 10.1016/j.aohep.2025.101781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 02/02/2025] [Indexed: 02/20/2025]
Abstract
Immunotherapy has revolutionized the treatment landscape for advanced HCC, resulting in prolonged response and improved survival. With these results, a pressing question arises: what is the optimal treatment following first-line immunotherapy? Despite the benefits of immunotherapy, most patients will experience disease progression within six months and will require subsequent therapies. International guidelines recommend second-line multi-kinase inhibitors following progression on immunotherapy; however, this recommendation is primarily based on expert consensus rather than high-quality evidence. Nevertheless, real-world data indicate that these agents demonstrate similar efficacy and safety when used as first-line treatments. Conversely, it remains unclear whether continuing immunotherapy after progression is beneficial. In some cases, adding anti-CTLA-4 as salvage therapy has shown effectiveness. Molecular-directed therapies have also been tested, showing some initial promise, but further data is needed to confirm the benefits of this approach. Emerging evidence suggests that patients experiencing oligoprogression may benefit from local or locoregional therapies while continuing immunotherapy. In this review, we will discuss treatment strategies following progression after first-line immunotherapy.
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Affiliation(s)
- Landon L Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Tsz Tung Kwong
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Johnny C W Yau
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Stephen L Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
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7
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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8
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Masuda S, Lemaitre F, Barten MJ, Bergan S, Shipkova M, van Gelder T, Vinks S, Wieland E, Bornemann-Kolatzki K, Brunet M, de Winter B, Dieterlen MT, Elens L, Ito T, Johnson-Davis K, Kunicki PK, Lawson R, Lloberas N, Marquet P, Millan O, Mizuno T, Moes DJAR, Noceti O, Oellerich M, Pattanaik S, Pawinski T, Seger C, van Schaik R, Venkataramanan R, Walson P, Woillard JB, Langman LJ. Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2025; 47:4-31. [PMID: 39331837 DOI: 10.1097/ftd.0000000000001250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/09/2024] [Indexed: 09/29/2024]
Abstract
ABSTRACT The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.
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Affiliation(s)
- Satohiro Masuda
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan
| | - Florian Lemaitre
- Université de Rennes, CHU Rennes, Inserm, EHESP, IRSET-UMR S 1085, Rennes, France
- INSERM, Centre d'Investigation Clinique 1414, Rennes, France
- FHU SUPPORT, Rennes, France
| | - Markus J Barten
- Department of Cardiac and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Norway
| | | | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sander Vinks
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- NDA Partners, A Propharma Group Company, Washington District of Columbia
| | | | | | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Brenda de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maja-Theresa Dieterlen
- Laboratory Management Research Laboratory, Cardiac Surgery Clinic, Heart Center Leipzig GmbH, University Hospital, Leipzig, Germany
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenetic and Pharmacokinetics Research Group (PMGK) Louvain Drug for Research Institute (LDRI), Catholic University of Louvain, (UCLouvain), Brussels, Belgium
| | - Taihei Ito
- Department of Organ Transplant Surgery; Fujita Health University School of Medicine, Toyoake Aichi, Japan
| | - Kamisha Johnson-Davis
- University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Pawel K Kunicki
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | - Roland Lawson
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
| | - Nuria Lloberas
- Nephrology Department, Hospital Universitari de Bellvitge-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Pierre Marquet
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, France
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ofelia Noceti
- National Center for Liver Transplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Smita Pattanaik
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Tomasz Pawinski
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | | | - Ron van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Phil Walson
- University Medical School, Göttingen, Germany
| | - Jean-Baptiste Woillard
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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9
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Lv J, Wang Y, Lv J, Zheng C, Zhang X, Wan L, Zhang J, Liu F, Zhang H. Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment. Cell Death Dis 2025; 16:42. [PMID: 39863613 PMCID: PMC11762308 DOI: 10.1038/s41419-025-07332-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 12/10/2024] [Accepted: 01/07/2025] [Indexed: 01/30/2025]
Abstract
TSC2, a suppressor of mTOR, is inactivated in up to 20% of HBV-associated liver cancer. This subtype of liver cancer is associated with aggressive behavior and early recurrence after hepatectomy. Being the first targeted regimen for advanced liver cancer, sorafenib has limited efficacy in HBV-positive patients. In this study, we observed that mTOR-activated cells, due to the loss of either TSC2 or PTEN, were insensitive to the treatment of sorafenib. Mechanistically, HSP70 enhanced the interaction between active mTOR-potentiated CREB1 and CREBBP to boost the transcription of the antioxidant response regulator SESN3. In return, elevated SESN3 enhanced cellular antioxidant capacity and rendered cells resistant to sorafenib. Pifithrin-μ, an HSP70 inhibitor, synergized with sorafenib in the induction of ferroptosis in mTOR-activated liver cancer cells and suppression of TSC2-deficient hepatocarcinogenesis. Our findings highlight the pivotal role of the mTOR-CREB1-SESN3 axis in sorafenib resistance of liver cancer and pave the way for combining pifithrin-μ and sorafenib for the treatment of mTOR-activated liver cancer.
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Affiliation(s)
- Jiarui Lv
- Department of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanan Wang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiacheng Lv
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Cuiting Zheng
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Zhang
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiology, State Key Laboratory of Complex, Severe and Rare Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College and Peking Union Medical College Hospital, Beijing, China
| | - Linyan Wan
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Gastroenterology, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
| | - Jiayang Zhang
- Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China
| | - Fangming Liu
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongbing Zhang
- Department of Organ Transplantation and Hepatobiliary Surgery, Key Laboratory of Organ Transplantation of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
- Department of Physiology, State Key Laboratory of Common Mechanism Research for Major Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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10
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Lee SB, Kim K. Correspondence to editorial on "KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression". Clin Mol Hepatol 2025; 31:e78-e80. [PMID: 39253744 PMCID: PMC11791590 DOI: 10.3350/cmh.2024.0750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/11/2024] Open
Affiliation(s)
- Sang Bae Lee
- Division of Life Sciences, Jeonbuk National University, Jeonju, Korea
| | - KyeongJin Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
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11
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Pol S. [Hepatocellular carcinoma (HCC)]. MEDECINE TROPICALE ET SANTE INTERNATIONALE 2024; 4:mtsi.v4i4.2024.614. [PMID: 40070978 PMCID: PMC11892391 DOI: 10.48327/mtsi.v4i4.2024.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/15/2024] [Indexed: 03/14/2025]
Abstract
Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.
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Affiliation(s)
- Stanislas Pol
- AP-HP. Centre Université Paris Centre, Groupe hospitalier Cochin Port Royal, Département médical universitaire de Cancérologie et spécialités médico-chirurgicales, Service des maladies du foie, Paris, France; Université Paris Cité, F-75006, Paris, France
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12
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Mehta D, Rajput K, Jain D, Bajaj A, Dasgupta U. Unveiling the Role of Mechanistic Target of Rapamycin Kinase (MTOR) Signaling in Cancer Progression and the Emergence of MTOR Inhibitors as Therapeutic Strategies. ACS Pharmacol Transl Sci 2024; 7:3758-3779. [PMID: 39698262 PMCID: PMC11650738 DOI: 10.1021/acsptsci.4c00530] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/08/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024]
Abstract
The mechanistic target of rapamycin kinase (MTOR) is pivotal for cell growth, metabolism, and survival. It functions through two distinct complexes, mechanistic TORC1 and mechanistic TORC2 (mTORC1 and mTORC2). These complexes function in the development and progression of cancer by regulating different cellular processes, such as protein synthesis, lipid metabolism, and glucose homeostasis. The mTORC1 complex senses nutrients and initiates proliferative signals, and mTORC2 is crucial for cell survival and cytoskeletal rearrangements. mTORC1 and mTORC2 have therefore emerged as potential targets for cancer treatment. Several mTOR inhibitors, including rapamycin and its analogs (rapalogs), primarily target mTORC1 and are effective for specific cancer types. However, these inhibitors often lead to resistance and limited long-term advantages due to the activation of survival pathways through feedback mechanisms. Researchers have created next-generation inhibitors targeting mTORC1 and mTORC2 and dual PI3K/mTOR inhibitors to address these difficulties. These inhibitors demonstrate enhanced anti-tumor effects by simultaneously disrupting multiple signaling pathways and show promise for improved and long-lasting therapies. However, development of resistance and adverse side effects remain a significant obstacle. Recent additions known as RapaLinks have emerged as a boon to counter drug-resistant cancer cells, as they are more potent and provide a more comprehensive blockade of mTOR signaling pathways. This Review combines current research findings and clinical insights to enhance our understanding of the crucial role of mTOR signaling in cancer biology and highlights the evolution of mTOR inhibitors as promising therapeutic approaches.
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Affiliation(s)
- Devashish Mehta
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
| | - Kajal Rajput
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
| | - Dolly Jain
- Laboratory
of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon
Expressway, Faridabad-121001, Haryana, India
| | - Avinash Bajaj
- Laboratory
of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon
Expressway, Faridabad-121001, Haryana, India
| | - Ujjaini Dasgupta
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
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13
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Wang Q, Yu J, Sun X, Li J, Cao S, Han Y, Wang H, Yang Z, Li J, Hu C, Zhang Y, Jin L. Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2024; 204:104522. [PMID: 39332750 DOI: 10.1016/j.critrevonc.2024.104522] [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: 07/21/2024] [Revised: 09/18/2024] [Accepted: 09/21/2024] [Indexed: 09/29/2024] Open
Abstract
PURPOSE For patients with advanced or unresectable hepatocellular carcinoma (HCC), safe and effective therapies are urgently needed to improve their long-term prognosis. Although the guidelines recommend first-line treatments such as sorafenib, lenvatinib, and atezolizumab in combination with bevacizumab (T+A) and second-line treatments such as regorafenib, the efficacy comparison between drugs is lacking, that is, a treatment is not recommended as the optimal or alternative choice for a specific patient population. Therefore, we will conduct a high-quality network meta-analysis based on Phase III randomized controlled trials (RCTs) to systematically evaluate and compare overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAE) of different treatment protocols in the context of first-line and second-line therapies, which are critical for clinical decision making and prognostic improvement in advanced HCC patients. METHODS The studies of interest were Phase III RCTs evaluating the efficacy or safety of first- or second-line therapies in patients with unresectable or advanced HCC. Literature published in English from the four databases of PubMed, Embase, Cochrane Library, and Web of Science was comprehensively searched from the inception to May 23, 2022. Outcomes of interest included OS, PFS, ORR, and SAE. A league table was developed to show the results of the comparison between different treatments. A histogram of cumulative probability was drawn to discuss the ranking probability of treatments based on different outcomes. The effectiveness and safety of various treatments were comprehensively considered and the two-dimensional diagram was plotted to guide clinical practice. The Gemtc package in R Studio was used for network meta-analysis in a Bayesian framework. RESULTS The results showed that HAIC-FO was superior to T+A regimen, regardless of OS, PFS or ORR. TACE combined with lenvatinib performed better than T+A in PFS, and ORR. In addition to the T+A regimen, Sintilimab combined with IBI305 and camrelizumab combined with apatinib were also associated with longer OS, PFS, and ORR, and their SAE incidence was not higher than that of T+A, especially for camrelizumab combined with apatinib, its safety was better than that of T+A regimen. There were no new treatments or combinations that were more effective than regorafenib. It was important to note that for PFS, the efficacy of apatinib and cabozantinib was not statistically different from that of regorafenib, so these two treatments could be used as alternative treatment options in cases where regorafenib was not tolerated or treatment failed. CONCLUSIONS We conducted a network meta-analysis to evaluate the efficacy and safety of multiple treatment modalities by integrating the results of direct and indirect comparisons. This study included high-quality multicenter Phase III RCTs, collated and summarized all treatments involved in advanced or unresectable HCC in first-line and second-line settings, and compared with T+A and regorafenib, respectively, and ranked based on efficacy and safety to support clinical decision making.
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Affiliation(s)
- Qi Wang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jianan Yu
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xuedong Sun
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jian Li
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shasha Cao
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yanjing Han
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Haochen Wang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zeran Yang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jianjun Li
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Caixia Hu
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Yonghong Zhang
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China.
| | - Long Jin
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
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14
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Lehrich BM, Tao J, Liu S, Hirsch TZ, Yasaka TM, Cao C, Delgado ER, Guan X, Lu S, Pan L, Liu Y, Singh S, Poddar M, Bell A, Singhi AD, Zucman-Rossi J, Wang Y, Monga SP. Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC. JHEP Rep 2024; 6:101186. [PMID: 39583094 PMCID: PMC11582745 DOI: 10.1016/j.jhepr.2024.101186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/26/2024] [Accepted: 08/05/2024] [Indexed: 11/26/2024] Open
Abstract
Background & Aims Patients with β-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of the Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients with HCC for future application in personalized medicine treatment regimens. Methods Co-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. The MBGS was derived using bulk RNA-seq and intersectional transcriptomic analysis of β-catenin-mutated and non-mutated HCC models. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple cohorts of patients with HCC was assessed to address the ability of MBGS to detect CTNNB1 mutation, the tumor immune microenvironment, and/or predict therapeutic responses. Results Bulk RNA-seq comparing HCC specimens in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In The Cancer Genome Atlas (TCGA)-LIHC dataset, differential gene expression analysis with false discovery rate (FDR) = 0.05 and log2(fold change) >1.5 on the 95 common genes comparing CTNNB1-mutated vs. wild-type patients narrowed the gene panel to a 13-gene MBGS. MBGS predicted CTNNB1-mutations in TCGA (n = 374) and French (n = 398) patient cohorts with AUCs of 0.90 and 0.94, respectively. Additionally, a higher MBGS expression score was associated with lack of significant improvement in overall survival or progression-free survival in the atezolizumab-bevacizumab arm vs. the sorafenib arm in the IMbrave150 cohort. MBGS performed comparable or superior to other CTNNB1-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment. Conclusions MBGS will aid in patient stratification to guide precision medicine therapeutics for CTNNB1-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available. Impact and implications As precision medicine for liver cancer treatment becomes a reality, diagnostic tools are needed to help classify patients into groups for the best treatment choices. We have developed a molecular signature that could serve as a companion diagnostic and uses bulk or spatial transcriptomic data to identify a unique subclass of liver tumors. This subgroup of liver cancer patients derive limited benefit from the current standard of care and are expected to benefit from specialized directed therapies that are on the horizon.
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Affiliation(s)
- Brandon M. Lehrich
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Junyan Tao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Silvia Liu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Theo Z. Hirsch
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Tyler M. Yasaka
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine Cao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Evan R. Delgado
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xiangnan Guan
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Shan Lu
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Long Pan
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Yuqing Liu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sucha Singh
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aaron Bell
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Aatur D. Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, Paris, France
- Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, Paris, France
| | - Yulei Wang
- Translational Medicine, Genentech Inc., San Francisco, CA, USA
| | - Satdarshan P. Monga
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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15
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Su CH, Chen CY, Liu CT, Yang YH, Wu PC. Hepatitis and Hepatitis B Virus Reactivation in Everolimus-Treated Solid Tumor Patients: A Focus on HBV-Endemic Areas. Cancers (Basel) 2024; 16:3997. [PMID: 39682184 DOI: 10.3390/cancers16233997] [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: 10/04/2024] [Revised: 11/06/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Everolimus is approved for treating breast, renal, and pancreatic neuroendocrine cancers but carries the risk of hepatitis B virus (HBV) reactivation (HBVr) and hepatitis. However, data on HBVr in everolimus-treated patients are limited. This study evaluates the risk of hepatitis and HBVr in cancer patients with current or past HBV infection. METHODS This retrospective study analyzed patients prescribed everolimus between 1 January 2011 and 31 May 2022, using a private healthcare system database in Taiwan. Patients with HBsAg positivity or HBsAg negativity and anti-HBs or anti-HBc results were included. The cumulative incidence function and risk of hepatitis from a competing risk model, which estimates Fine-Gray subdistribution hazard (SDH), were analyzed across different HBV serological subgroups. The risk of hepatitis B reactivation was also calculated. RESULTS Of 377 patients, 45% (36/80) of HBsAg-positive and 0.67% (2/297) of HBsAg-negative patients received nucleos(t)ide analogues (NUCs) prophylaxis. Hepatitis occurred in 28.75% of HBsAg-positive and 17.85% of HBsAg-negative patients. Baseline HBsAg positivity and exemestane use increased hepatitis risk. HBVr occurred in 11.36% (5/44) of HBsAg-positive patients without NUCs and 5.56% (2/36) with prophylaxis. Two HBsAg-negative, anti-HBc-positive patients developed severe HBVr-related hepatitis. CONCLUSION Hepatitis occurred in 28.75% of HBsAg-positive and 17.85% of HBsAg-negative patients on everolimus. HBVr was common in HBsAg-positive patients but rare in HBsAg-negative individuals. HBV screening and liver function monitoring are critical for patients with past or current HBV infection receiving everolimus, especially in endemic areas.
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Affiliation(s)
- Chien-Hao Su
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Pharmacy, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Chung-Yu Chen
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chien-Ting Liu
- Division of Hematology-Oncology, Department of Internal Medicine, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yi-Hsin Yang
- National Institute of Cancer Research, National Health Research Institutes, No. 367, Sheng-Li Rd., North District, Tainan 704, Taiwan
| | - Pao-Chu Wu
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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16
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Jung YH, Lee YJ, Dao T, Jung KH, Yu J, Oh AR, Jeong Y, Gi H, Kim YU, Ryu D, Carrer M, Pajvani UB, Lee SB, Hong SS, Kim K. KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression. Clin Mol Hepatol 2024; 30:895-913. [PMID: 39098817 PMCID: PMC11540369 DOI: 10.3350/cmh.2024.0364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND/AIMS Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression. METHODS We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo. RESULTS Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice. CONCLUSION KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
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Affiliation(s)
- Young Hoon Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yun Ji Lee
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Tam Dao
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Kyung Hee Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, NY, USA
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China
| | - Ah-Reum Oh
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yelin Jeong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - HyunJoon Gi
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Young Un Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | | | | | - Sang Bae Lee
- Division of Life Sciences, Jeonbuk National University, Jeonju, Korea
| | - Soon-Sun Hong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - KyeongJin Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
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17
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Wang T, Takikawa Y, Suzuki K, Kuroda H, Kakisaka K, Chiba T. Comparative analysis of sorafenib and lenvatinib on HepG2 cells and human umbilical vein endothelial cells: Involvement of transforming growth factor-β signaling in their molecular effects. Hepatol Res 2024; 54:921-930. [PMID: 38666637 DOI: 10.1111/hepr.14045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/02/2024] [Accepted: 03/14/2024] [Indexed: 10/02/2024]
Abstract
AIM This study aimed to compare the effects of the molecular targeted drugs, sorafenib and lenvatinib, on the survival, invasion, and angiogenesis of hepatocellular carcinoma cells. Additionally, we investigated the involvement of transforming growth factor beta (TGF-β) signaling in their molecular mechanisms. METHODS To investigate the effects of sorafenib and lenvatinib, we conducted cell viability, invasion, and angiogenesis assays, as well as western blotting analyses. RESULTS In human hepatocellular carcinoma cells (HepG2), sorafenib demonstrated potent inhibitory effects on cell proliferation, but induced cell invasion similar to TGF-β. In contrast, lenvatinib showed weaker cytotoxicity compared with sorafenib, but suppressed cell invasion induced by TGF-β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the TGFβR2/ERK pathway. Moreover, in human umbilical vein endothelial cells, Sorafenib showed weaker cytotoxicity and enhanced the effects of TGF-β on angiogenesis. Conversely, lenvatinib showed potent cytotoxic abilities and suppressed angiogenesis induced by TGF-β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the crosstalk between TGF-β signaling and vascular endothelial growth factor signaling. CONCLUSIONS Our findings indicate that both sorafenib and lenvatinib possess anticancer abilities by inducing the cytotoxicity of hepatocellular carcinoma cells. Furthermore, they show opposing effects on TGF-β-induced cell invasion and angiogenesis, thereby enhancing the understanding of the multifaceted functions of molecular targeted drugs in treating hepatocellular carcinoma.
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Affiliation(s)
- Ting Wang
- Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University, Morioka, Iwate, Japan
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Kazuyuki Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Iwate, Japan
| | - Toshimi Chiba
- Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University, Morioka, Iwate, Japan
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18
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Testa U. Recent developments in molecular targeted therapies for hepatocellular carcinoma in the genomic era. Expert Rev Mol Diagn 2024; 24:803-827. [PMID: 39194003 DOI: 10.1080/14737159.2024.2392278] [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: 04/03/2024] [Accepted: 08/11/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Primary liver cancer is a major health problem being the sixth most frequent cancer in the world and the third cause of cancer-related death in the world. The most common histological type of liver cancer is hepatocellular carcinoma (HCC, 75-80%). AREAS COVERED Based on primary literature, this review provides an updated analysis of studies of genetic characterization of HCC at the level of gene mutation profiling, copy number alterations, and gene expression, with the definition of molecular subgroups and the identification of some molecular biomarkers and therapeutic targets. Recent therapeutic developments are also highlighted. EXPERT OPINION Deepening the understanding of the molecular complexity of HCC is progressively paving the way for the development of more personalized treatment approaches. Two important strategies involve the definition and validation of molecularly defined therapeutic targets in a subset of HCC patients and the identification of suitable biomarkers for approved systematic therapies (multikinase inhibitors and immunotherapies). The extensive molecular characterization of patients at the genomic and transcriptomic levels and the inclusion of detailed and relevant translational studies in clinical trials will represent a fundamental tool for improving the benefit of systemic therapies in HCC.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Rome, Italy
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Zhao W, Wang X, Han L, Zhang C, Wang C, Kong D, Zhang M, Xu T, Li G, Hu G, Luo J, Yee SW, Yang J, Stahl A, Chen X, Zhang Y. SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis. Nat Commun 2024; 15:7522. [PMID: 39215042 PMCID: PMC11364541 DOI: 10.1038/s41467-024-51860-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Activated Wnt/β-catenin pathway is a key genetic event in liver cancer development. Solute carrier (SLC) transporters are promising drug targets. Here, we identify SLC13A3 as a drug-targetable effector downstream of β-catenin in liver cancer. SLC13A3 expression is elevated in human liver cancer samples with gain of function (GOF) mutant CTNNB1, the gene encoding β-catenin. Activation of β-catenin up-regulates SLC13A3, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of SLC13A3 downregulates the leucine transporter SLC7A5 via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of SLC13A3 depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of SLC13A3 and a small molecule SLC13A3 inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice. Altogether, our study suggests that SLC13A3 could be a promising therapeutic target for treating human liver cancers with GOF CTNNB1 mutations.
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Affiliation(s)
- Wennan Zhao
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Xue Wang
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Chenxi Wang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Mingzhe Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Tong Xu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Gen Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Ge Hu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Jiahua Luo
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Sook Wah Yee
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Jia Yang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Andreas Stahl
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA
| | - Xin Chen
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
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Raghav A, Jeong GB. Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. Int J Mol Sci 2024; 25:9286. [PMID: 39273237 PMCID: PMC11395253 DOI: 10.3390/ijms25179286] [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: 06/06/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013-2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations.
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Affiliation(s)
- Alok Raghav
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
| | - Goo Bo Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
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Lu F, Zhao K, Ye M, Xing G, Liu B, Li X, Ran Y, Wu F, Chen W, Hu S. Efficacy and safety of second-line therapies for advanced hepatocellular carcinoma: a network meta-analysis of randomized controlled trials. BMC Cancer 2024; 24:1023. [PMID: 39160484 PMCID: PMC11331808 DOI: 10.1186/s12885-024-12780-y] [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: 06/01/2024] [Accepted: 08/07/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC). METHODS We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability. RESULTS We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures. CONCLUSIONS Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.
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Affiliation(s)
- Fenping Lu
- Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Kai Zhao
- Shaanxi Shuangbo Hospital of Traditional Chinese Medicine for Liver and Kidney Diseases, Xi'an, China
| | - Miaoqing Ye
- Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Guangyan Xing
- Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Bowen Liu
- Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Xiaobin Li
- Beijing University of Chinese Medicine, Beijing, China
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Yun Ran
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Fenfang Wu
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China
| | - Wei Chen
- Department of Pharmacy, Emergency General Hospital, Beijing, China
| | - Shiping Hu
- Beijing University of Chinese Medicine Affiliated Shenzhen Hospital, Shenzhen, China.
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22
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Chen K, Shuen TWH, Chow PKH. The association between tumour heterogeneity and immune evasion mechanisms in hepatocellular carcinoma and its clinical implications. Br J Cancer 2024; 131:420-429. [PMID: 38760445 PMCID: PMC11300599 DOI: 10.1038/s41416-024-02684-w] [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: 12/15/2023] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 05/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The emergence of combination therapy, atezolizumab (anti-PDL1, immune checkpoint inhibitor) and bevacizumab (anti-VEGF) has revolutionised the management of HCC. Despite this breakthrough, the best overall response rate with first-line systemic therapy is only about 30%, owing to intra-tumoural heterogeneity, complex tumour microenvironment and the lack of predictive biomarkers. Many groups have attempted to classify HCC based on the immune microenvironment and have consistently observed better outcomes in immunologically "hot" HCC. We summarised possible mechanisms of tumour immune evasion based on the latest literature and the rationale for combination/sequential therapy to improve treatment response. Lastly, we proposed future strategies and therapies to overcome HCC immune evasion to further improve treatment outcomes of HCC.
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Affiliation(s)
- Kaina Chen
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Timothy W H Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Pierce K H Chow
- Duke-NUS Medical School, Singapore, Singapore.
- Department of Hepato-pancreato-biliary and Transplant Surgery, National Cancer Centre Singapore and Singapore General Hospital, Singapore, Singapore.
- Program in Translational and Clinical Liver Cancer Research, National Cancer Centre Singapore, Singapore, Singapore.
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Himmelsbach V, Jeschke M, Lange CM, Scheiner B, Pinter M, Sinner F, Venerito M, Queck A, Trojan J, Waidmann O, Finkelmeier F. Systemic Treatment of Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Multicenter Trial. Cancers (Basel) 2024; 16:2442. [PMID: 39001504 PMCID: PMC11240676 DOI: 10.3390/cancers16132442] [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: 05/24/2024] [Revised: 06/24/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
INTRODUCTION The tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib represent the first-line systemic therapy of choice for patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Under sorafenib and lenvatinib, HCC patients have shown increasingly improved overall survival in clinical studies over the years. In contrast, data on overall survival for patients with HCC recurrence after LT under TKIs are scarce and limited to small retrospective series. In this retrospective, multicenter study, we investigated the efficacy of TKI therapy and the influence of immunosuppression in patients with HCC recurrence after LT. METHODS Retrospective data were collected from four transplant centers from Germany and Austria. We included patients with HCC recurrence after LT between 2007 and 2020 who were treated with a TKI. RESULTS In total, we analyzed data from 46 patients with HCC recurrence after LT. The most common underlying liver disease was hepatitis C, accounting for 52.2%. The median time to relapse was 11.8 months (range 0-117.7 months). The liver graft was affected in 21 patients (45.7%), and 36 patients (78.3%) had extrahepatic metastases at initial diagnosis of recurrence, with the lung being the most commonly affected (n = 25, 54.3%). Of the total, 54.3% (n = 25) of the patients were initially treated locally; 39 (85.8%) and 7 (15.2%) patients received sorafenib and lenvatinib, respectively, as first-line systemic therapy. Median overall survival of the whole cohort was 10.9 months (95% confidence interval (95% CI) 6.9-14.9 months) and median progression free survival was 5.7 months (95% CI 2.0-9.4 months) from treatment initiation. CONCLUSION Since history of liver transplantation is considered a contraindication for immunotherapy, prognosis of patients with HCC recurrence after LT remains poor.
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Affiliation(s)
- Vera Himmelsbach
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, 60590 Frankfurt, Germany
| | - Matthias Jeschke
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, 45147 Essen, Germany
| | - Christian M. Lange
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, 45147 Essen, Germany
- Department of Medicine II, University Hospital, Ludwig-Maximilian University, 81377 Munich, Germany
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Friedrich Sinner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, 39120 Magdeburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, 39120 Magdeburg, Germany
| | - Alexander Queck
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, 60590 Frankfurt, Germany
| | - Jörg Trojan
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, 60590 Frankfurt, Germany
| | - Oliver Waidmann
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, 60590 Frankfurt, Germany
- Center of Hematology and Oncology Bethanien, 60389 Frankfurt, Germany
| | - Fabian Finkelmeier
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, 60590 Frankfurt, Germany
- University Cancer Center Frankfurt, University Hospital Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe University Frankfurt/Main, 60438 Frankfurt, Germany
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24
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [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: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [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: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
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Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
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Tang H, Dilimulati D, Yang Z, Zhou K, Chen X, Sun R, Wang N, Liang Z, Bian S, Zhao J, Song P, Zheng S, Wang H, Xie H. Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy. EBioMedicine 2024; 103:105099. [PMID: 38604089 PMCID: PMC11017279 DOI: 10.1016/j.ebiom.2024.105099] [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: 08/30/2023] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).
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Affiliation(s)
- Hong Tang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Dilinuer Dilimulati
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province 310003, China
| | - Zhentao Yang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ke Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xiaona Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ruiqi Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ning Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhi Liang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Suchen Bian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jialing Zhao
- Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province 310003, China
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province 310003, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province 310003, China.
| | - Hangxiang Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province 310003, China.
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Wang F, Xu WQ, Zhang WQ, Xu RC, Sun JL, Zhang GC, Liu ZY, Qi ZR, Dong L, Weng SQ, Shen XZ, Liu TT, Fang Y, Zhu JM. Transferrin receptor 1 promotes hepatocellular carcinoma progression and metastasis by activating the mTOR signaling pathway. Hepatol Int 2024; 18:636-650. [PMID: 37982952 DOI: 10.1007/s12072-023-10607-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/09/2023] [Indexed: 11/21/2023]
Abstract
BACKGROUND Aberrant iron metabolism is commonly observed in multiple tumor types, including hepatocellular carcinoma (HCC). However, as the key regulator of iron metabolism involved in iron absorption, the role of transferrin receptor (TFRC) in HCC remains elusive. METHODS The mRNA and protein expression of TFRC were evaluated in paired HCC and adjacent non-tumor specimens. The correlation between TFRC level and clinicopathological features or prognostic significance was also analyzed. The role of TFRC on biological functions was finally studied in vitro and in vivo. RESULTS The TFRC level was remarkably upregulated in HCC tissues compared to paired peritumor tissues. Overexpressed TFRC positively correlated with serum alpha-fetoprotein, carcinoembryonic antigen, and poor tumor differentiation. Multivariate analysis demonstrated that upregulated TFRC was an independent predictive marker for poorer overall survival and disease-free survival in HCC patients. Loss of TFRC markedly impaired cell proliferation and migration in vitro and notably suppressed HCC growth and metastasis in vivo, while overexpression of TFRC performed an opposite effect. Mechanistically, the mTOR signaling pathway was downregulated with TFRC knockdown, and the mTOR agonist MHY1485 completely reversed the biological inhibition in HCC cells caused by TFRC knockdown. Furthermore, exogenous ferric citrate (FAC) or iron chelator reversed the changed biological functions and signaling pathway expression of HCC cells caused by TFRC knockdown or overexpression, respectively. CONCLUSIONS Our study indicates that TFRC exerts an oncogenic role in HCC and may become a promising therapeutic target to restrain HCC progression.
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Affiliation(s)
- Fu Wang
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Wei-Qi Xu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wan-Qin Zhang
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Ru-Chen Xu
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Jia-Lei Sun
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Guang-Cong Zhang
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Zhi-Yong Liu
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Zhuo-Ran Qi
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Ling Dong
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Shu-Qiang Weng
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, 138 Yixueyuan Rd., Shanghai, 200032, China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China
| | - Ying Fang
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China.
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai, 200032, China.
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Cabibbo G, Daniele B, Borzio M, Casadei-Gardini A, Cillo U, Colli A, Conforti M, Dadduzio V, Dionisi F, Farinati F, Gardini I, Giannini EG, Golfieri R, Guido M, Mega A, Cinquini M, Piscaglia F, Rimassa L, Romanini L, Pecorelli A, Sacco R, Scorsetti M, Viganò L, Vitale A, Trevisani F. Multidisciplinary treatment of hepatocellular carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) - Part II - Non-surgical treatments. Dig Liver Dis 2024; 56:394-405. [PMID: 38052656 DOI: 10.1016/j.dld.2023.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/13/2023] [Accepted: 10/30/2023] [Indexed: 12/07/2023]
Abstract
Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.
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Affiliation(s)
- Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties PROMISE, University of Palermo, Gastroenterology Unit, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", Palermo, Italy.
| | - Bruno Daniele
- Oncology Unit, Ospedale del Mare, ASL Napoli 1 Centro, Napoli, Italy
| | - Mauro Borzio
- Centro Diagnostico Italiano (CDI), Milano, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Umberto Cillo
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Padua University Hospital, 35128 Padua, Italy
| | - Agostino Colli
- Dipartimento di Medicina Trasfusionale ed Ematologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | | | - Vincenzo Dadduzio
- Medical Oncology Unit, "Mons. A.R.Dimiccoli" Hospital, Barletta, ASL BT, Italy
| | - Francesco Dionisi
- Department of Radiation Oncology, IRCCS Regina Elena National Cancer Institute - Rome, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; Gastroenterology Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy
| | - Ivan Gardini
- EpaC Onlus, Italian Liver Patient Association, Turin, Italy
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Rita Golfieri
- Alma Mater Studiorum" Bologna University, Bologna, Italy; Radiology Unit Madre Fortunata Toniolo Private Hospital, coordinator of Radiology centers Medipass Bologna, Bologna, Italy
| | - Maria Guido
- Department of Medicine, University of Padova, Padova - Italy
| | - Andrea Mega
- Department of Gastronterology, Regional Hospital Bolzano, Italy
| | - Michela Cinquini
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Milano, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Laura Romanini
- Radiology Unit, Ospedale di Cremona, ASST Cremona, Cremona, Italy
| | - Anna Pecorelli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Rodolfo Sacco
- Gastroenterology and Endoscopy Unit, Department of Surgical and Medical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Marta Scorsetti
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Milan, Italy; Department of Radiotherapy and Radiosurgery, Humanitas Research Hospital IRCCS, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Luca Viganò
- Hepatobiliary Unit, Department of Minimally Invasive General & Oncologic Surgery, Humanitas Gavazzeni University Hospital, Viale M. Gavazzeni 21, 24125 Bergamo, Italy; Department of Biomedical Sciences, Humanitas University, Viale Rita Levi Montalcini 4, 20090 Milan, Italy
| | - Alessandro Vitale
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Padua University Hospital, 35128 Padua, Italy
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, University of Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
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Cao R, Guo S, Min L, Li P. Roles of Rictor alterations in gastrointestinal tumors (Review). Oncol Rep 2024; 51:37. [PMID: 38186315 PMCID: PMC10807360 DOI: 10.3892/or.2024.8696] [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: 04/05/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024] Open
Abstract
Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re‑sensitization of therapy‑resistant cancers to be made possible.
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Affiliation(s)
- Ruizhen Cao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Shuilong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
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30
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Huang H, Yan J, Xu X, Feng Y, Liu H, Liu J, Xie M, Chen L, Xiang D, Peng W, Zeng L, Zeng Y, Chen F, Zhang S, Liu Q. Everolimus inhibits hepatoblastoma by inducing autophagy-dependent ferroptosis. Drug Dev Res 2024; 85:e22140. [PMID: 38349263 DOI: 10.1002/ddr.22140] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/22/2023] [Accepted: 12/08/2023] [Indexed: 02/15/2024]
Abstract
Everolimus, a known inhibitor of the mammalian target of rapamycin (mTOR), has shown uncertain efficacy in treating hepatoblastoma. This study delves into the potential anti-hepatoblastoma properties of everolimus and its intricate relationship with autophagy and ferroptosis, both in vitro and in vivo. In vivo, tumor tissue from hepatoblastoma patient and human hepatoblastoma cell line HuH-6 were xenografted into nude mice to establish xenograft models for observing the effect of everolimus on tumor growth. In vitro, HuH-6 cells were cultured to evaluate the anti-hepatoblastoma activity of everolimus. Transmission electron microscopy and microtubule-associated proteins 1 light chain 3 (LC3), beclin 1, and p62 protein expressions were employed to investigate autophagy. Additionally, indicators of cell apoptosis, reactive oxygen species (ROS) and proteins associated with ferroptosis were measured to evaluate ferroptosis. The results demonstrate that everolimus treatment effectively induced the formation of autophagosomes in hepatoblastoma cells, upregulated the LC3II/I ratio and beclin 1 expression, and downregulated p62 expression, indicating an enhanced autophagy level both in vitro and in vivo. Furthermore, everolimus treatment induced cell apoptosis, increased ROS level, elevated concentrations of malondialdehyde, 4-hydroxynonenal, and iron content, while reducing the ratio of glutathione/oxidized glutathione, and downregulating the protein expression of glutathione peroxidase 4 and solute carrier family 7 member 11, suggesting its ability to induce ferroptosis in hepatoblastoma cells. Importantly, the induction of ferroptosis by everolimus was significantly reversed in the presence of autophinib, an autophagy inhibitor, indicating the autophagy-dependent of everolimus-induced ferroptosis. Taken together, these findings suggest that everolimus holds promise as an effective anti-hepatoblastoma drug, with its mechanism of action potentially involving the induction of autophagy-dependent ferroptosis in hepatoblastoma cells.
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Affiliation(s)
- Haijin Huang
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Jiangxi Provincial Clinical Research Center for Vascular Anomalies, The First Affiliated Hospital of GanNan Medical University, Ganzhou, Jiangxi, China
| | - Jinlong Yan
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xianyun Xu
- Department of Clinical Laboratory, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, China
| | - Yanping Feng
- Department of Neurological Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Haijin Liu
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jianping Liu
- Department of General Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Mingfeng Xie
- Jiangxi Provincial Clinical Research Center for Vascular Anomalies, The First Affiliated Hospital of GanNan Medical University, Ganzhou, Jiangxi, China
- Chinese & Western Integrative Medicine Discipline, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- Jiangxi Key Laboratory of TCM for Prevention and Treatment on Hemangioma, Nanchang, Jiangxi, China
- Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Leifeng Chen
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Deng Xiang
- Department of General Surgery, The Affiliated Children's Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Wei Peng
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Linshan Zeng
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yong Zeng
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Feng Chen
- Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shouhua Zhang
- Department of General Surgery, The Affiliated Children's Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Qian Liu
- Jiangxi Provincial Clinical Research Center for Vascular Anomalies, The First Affiliated Hospital of GanNan Medical University, Ganzhou, Jiangxi, China
- Chinese & Western Integrative Medicine Discipline, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- Jiangxi Key Laboratory of TCM for Prevention and Treatment on Hemangioma, Nanchang, Jiangxi, China
- Integrated Chinese and Western Medicine Institute for Children Health & Drug Innovation, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
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31
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Chen C, Li Z, Xiong X, Yao A, Wang S, Liu X, Liu X, Wang J. Intraperitoneal PD-1 monoclonal antibody for the treatment of advanced primary liver cancer with malignant ascites: a single-arm, single-center, phase Ib trial. ESMO Open 2024; 9:102206. [PMID: 38194882 PMCID: PMC10820330 DOI: 10.1016/j.esmoop.2023.102206] [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: 10/18/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Advanced primary liver cancer patients with malignant ascites have a poor prognosis and lack effective treatment plans. This phase Ib study aims to explore the safety and clinical efficacy of intraperitoneal anti-programmed cell death protein 1 (PD-1) antibody in these patients. PATIENTS AND METHODS Patients received sintilimab 100 mg intraperitoneally plus best supportive care on days 1, 8, and 15 in three cycles of 4 weeks. The course was repeated every 28 days until intolerable toxicity had developed or disease progression. The primary endpoint was safety, while the secondary endpoints were objective response rate (ORR), ascites control rate (ACR), and overall survival (OS). RESULTS From February 2021 through November 2022, a total of 21 patients (14 hepatocellular carcinoma and 7 cholangiocarcinoma) were enrolled to receive intraperitoneal sintilimab. Twelve patients had adverse events (AEs). The most common grade 3 AEs were fatigue, rash, and abdominal pain. No grade ≥4 AEs occurred in any patients. ORR was only evaluated in 13 patients, including partial response in 4, stable disease in 7, and progressive disease in 2. A reduction in the median maximum diameter of the tumor after treatment was observed; however, there was no statistical significance among patients. The objective remission rate of ascites was 43.75%, and the median OS for all 21 patients was 17.6 weeks. CONCLUSIONS This exploratory study represents the first trial to demonstrate the safety and clinical efficacy of intraperitoneal anti-PD-1 antibody administration. No unexpected safety concerns were identified. A large, multicenter, prospective study is needed to confirm the promising clinical efficacy.
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Affiliation(s)
- C Chen
- Department of Oncology, Jinling Hospital, Nanjing Medical University, Nanjing
| | - Z Li
- Department of Oncology, Jinling Hospital, Nanjing Medical University, Nanjing
| | - X Xiong
- Department of Hepatology, Jinling Hospital, Nanjing Medical University, Nanjing
| | - A Yao
- Department of Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing
| | - S Wang
- Department of Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing
| | - X Liu
- Department of Oncology, Jinling Hospital, Nanjing Medical University, Nanjing
| | - X Liu
- Department of Oncology, Jinling Hospital, Nanjing Medical University, Nanjing.
| | - J Wang
- Department of Hematology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing; Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng, PR China.
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32
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Kroh A, Walter J, Fragoulis A, Möckel D, Lammers T, Kiessling F, Andruszkow J, Preisinger C, Egbert M, Jiao L, Eickhoff RM, Heise D, Berndt N, Cramer T, Neumann UP, Egners A, Ulmer TF. Hepatocellular loss of mTOR aggravates tumor burden in nonalcoholic steatohepatitis-related HCC. Neoplasia 2023; 46:100945. [PMID: 37976569 PMCID: PMC10685311 DOI: 10.1016/j.neo.2023.100945] [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: 07/08/2023] [Accepted: 10/13/2023] [Indexed: 11/19/2023]
Abstract
Obesity and associated nonalcoholic steatohepatitis (NASH) are on the rise globally. NASH became an important driver of hepatocellular carcinoma (HCC) in recent years. Activation of the central metabolic regulator mTOR (mechanistic target of rapamycin) is frequently observed in HCCs. However, mTOR inhibition failed to improve the outcome of HCC therapies, demonstrating the need for a better understanding of the molecular and functional consequences of mTOR blockade. We established a murine NASH-driven HCC model based on long-term western diet feeding combined with hepatocellular mTOR-inactivation. We evaluated tumor load and whole-body fat percentage via µCT-scans, analyzed metabolic blood parameters and tissue proteome profiles. Additionally, we used a bioinformatic model to access liver and HCC mitochondrial metabolic functions. The tumor burden was massively increased via mTOR-knockout. Several signs argue for extensive metabolic reprogramming of glucose, fatty acid, bile acid and cholesterol metabolism. Kinetic modeling revealed reduced oxygen consumption in KO-tumors. NASH-derived HCC pathogenesis is driven by metabolic disturbances and should be considered separately from those caused by other etiologies. We conclude that mTOR functions as tumor suppressor in hepatocytes especially under long-term western diet feeding. However, some of the detrimental consequences of this diet are attenuated by mTOR blockade.
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Affiliation(s)
- Andreas Kroh
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
| | - Jeanette Walter
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany
| | - Athanassios Fragoulis
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital Aachen, Germany
| | - Diana Möckel
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Twan Lammers
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Fabian Kiessling
- Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Aachen, Germany
| | - Julia Andruszkow
- Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Christian Preisinger
- Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF) Aachen, Medical School, RWTH Aachen University Hospital, Aachen, Germany
| | - Maren Egbert
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Long Jiao
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Roman M Eickhoff
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Nikolaus Berndt
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany; Institute of Computer-assisted Cardiovascular Medicine, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Antje Egners
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
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Yu J, Ling S, Hong J, Zhang L, Zhou W, Yin L, Xu S, Que Q, Wu Y, Zhan Q, Bao J, Xu N, Liu Y, Chen K, Wei X, Liu Z, Feng T, Zhou L, Xie H, Wang S, Liu J, Zheng S, Xu X. TP53/mTORC1-mediated bidirectional regulation of PD-L1 modulates immune evasion in hepatocellular carcinoma. J Immunother Cancer 2023; 11:e007479. [PMID: 38030304 PMCID: PMC10689408 DOI: 10.1136/jitc-2023-007479] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Immunotherapy has facilitated great breakthroughs in the treatment of hepatocellular carcinoma (HCC). However, the efficacy and response rate of immunotherapy are limited and vary among different patients with HCC. TP53 mutation substantially affects the expression of immune checkpoint molecules in multiple cancers. However, the regulatory relationship between programmed death ligand 1 (PD-L1) and TP53 is poorly studied in HCC. We aimed to elucidate the regulatory mechanism of PD-L1 in HCC with different TP53 statuses and to assess its role in modulating immune evasion in HCC. METHODS HCC mouse models and cell lines with different TP53 statuses were constructed. PD-L1 levels were detected by PCR, western blotting and flow cytometry. RNA-seqencing, immunoprecipitation, chromatin immunoprecipitation and transmission electron microscopy were used to elucidate the regulatory mechanism in HCC with different TP53 status. HCC mouse models and patient with HCC samples were analyzed to demonstrate the preclinical and clinical significance of the findings. RESULTS We report that loss of p53 promoted PD-L1 expression and reduced CD8+ T-cell infiltration in patient with HCC samples and mouse models. Mammalian target of rapamycin (mTOR) pathway was activated in p53-loss-of-function HCC or after knocking down TP53. The transcription factor E2F1 was found to bind to the p53 protein in TP53 wild-type HCC cells, and inhibiting mammalian target of rapamycin complex 1 (mTORC1) disrupted this binding and enhanced E2F1 translocation to the nucleus, where it bound to the PD-L1 promoter and transcriptionally upregulated PD-L1. In p53-loss-of-function HCC cells, autophagosomes were activated after mTORC1 suppression, promoting the degradation of PD-L1 protein. The combination of mTOR inhibitor and anti-PD-L1 antibody enhanced CD8+ T-cell infiltration and tumor suppression in TP53 wild-type HCC mouse models, but no benefit was observed in p53-loss-of-function HCC mouse models. In patients with TP53 wild-type HCC, PD-L1 levels were significantly higher in the high E2F1 group than in the low E2F1 group, and the low E2F1 level group had significantly superior survival. CONCLUSION We revealed the bidirectional regulatory mechanism of PD-L1 mediated by TP53/mTORC1 in HCC. The combination of mTOR inhibitor and anti-PD-L1 antibody could be a novel precise immunotherapy scheme for TP53 wild-type HCC.
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Affiliation(s)
- Jiongjie Yu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Sunbin Ling
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | | | - Lincheng Zhang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Wei Zhou
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Lu Yin
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Shengjun Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Qingyang Que
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Yongfeng Wu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Qifan Zhan
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiaqi Bao
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Nan Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Yuchen Liu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kangchen Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Zhikun Liu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Tingting Feng
- Department of Colorectal Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shuai Wang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Shusen Zheng
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
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Requeijo C, Bracchiglione J, Meza N, Acosta-Dighero R, Salazar J, Santero M, Meade AG, Quintana MJ, Rodríguez-Grijalva G, Selva A, Solà I, Urrútia G, Bonfill Cosp X, On behalf of Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group. Anticancer Drugs Compared to No Anticancer Drugs in Patients with Advanced Hepatobiliary Cancer: A Mapping Review and Evidence Gap Map. Clin Epidemiol 2023; 15:1069-1085. [PMID: 38025841 PMCID: PMC10644842 DOI: 10.2147/clep.s431498] [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: 07/20/2023] [Accepted: 10/14/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Despite being commonly recommended, the impact of anticancer drugs (ACDs) on patient-important outcomes beyond survival for advanced hepatobiliary cancers (HBCs) may not have been sufficiently assessed. We aim to identify and map the evidence regarding ACDs versus best supportive care (BSC) for advanced HBCs, considering patient-centered outcomes. Methods In this mapping review, we included systematic reviews, randomized controlled trials, quasi-experimental, and observational studies comparing ACDs (chemotherapy, immunotherapy, biological/targeted therapy) versus BSC for advanced HBCs. We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Library, Epistemonikos, PROSPERO and clinicaltrials.gov for eligible studies. Two reviewers performed the screening and data extraction processes. We developed evidence maps for each type of cancer. Results We included 87 studies (60 for advanced liver cancer and 27 for gallbladder or bile duct cancers). Most of the evidence favored ACDs for survival outcomes, and BSC for toxicity. We identified several evidence gaps for non-survival outcomes, including quality of life or quality of end-of-life care. Discussion Patient-important outcomes beyond survival in advanced HBCs are insufficiently assessed by the available evidence. Future studies need to address these gaps to better inform decision-making processes.
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Affiliation(s)
- Carolina Requeijo
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Javier Bracchiglione
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Nicolás Meza
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
| | - Roberto Acosta-Dighero
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
| | - Josefina Salazar
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Adriana-G Meade
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - María Jesús Quintana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | | | - Anna Selva
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Parc Taulí Research and Innovation Institute Foundation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain
| | - Ivan Solà
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Gerard Urrútia
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
| | - Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - On behalf of Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile
- CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
- Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Parc Taulí Research and Innovation Institute Foundation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain
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Bicer F, Kure C, Ozluk AA, El-Rayes BF, Akce M. Advances in Immunotherapy for Hepatocellular Carcinoma (HCC). Curr Oncol 2023; 30:9789-9812. [PMID: 37999131 PMCID: PMC10670350 DOI: 10.3390/curroncol30110711] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths in the world. More than half of patients with HCC present with advanced stage, and highly active systemic therapies are crucial for improving outcomes. Immune checkpoint inhibitor (ICI)-based therapies have emerged as novel therapy options for advanced HCC. Only one third of patients achieve an objective response with ICI-based therapies due to primary resistance or acquired resistance. The liver tumor microenvironment is naturally immunosuppressive, and specific mutations in cell signaling pathways allow the tumor to evade the immune response. Next, gene sequencing of the tumor tissue or circulating tumor DNA may delineate resistance mechanisms to ICI-based therapy and provide a rationale for novel combination therapies. In this review, we discuss the results of key clinical trials that have led to approval of ICI-based therapy options in advanced HCC and summarize the ongoing clinical trials. We review resistance mechanisms to ICIs and discuss how immunotherapies may be optimized based on the emerging research of tumor biomarkers and genomic alterations.
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Affiliation(s)
- Fuat Bicer
- Division of Hematology Oncology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA;
| | - Catrina Kure
- Department of Medicine, Northside Hospital-Gwinnett, Lawrenceville, GA 30046, USA;
| | - Anil A. Ozluk
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Bassel F. El-Rayes
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
| | - Mehmet Akce
- Division of Hematology Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA; (A.A.O.); (B.F.E.-R.)
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Wang K, Xiang YJ, Yu HM, Cheng YQ, Feng JK, Liu ZH, Shan YF, Zheng YT, Ni QZ, Cheng SQ. Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation. BMC Cancer 2023; 23:1017. [PMID: 37867191 PMCID: PMC10591394 DOI: 10.1186/s12885-023-11485-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 10/06/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.
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Affiliation(s)
- Kang Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Hong-Ming Yu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jin-Kai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yun-Feng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yi-Tao Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qian-Zhi Ni
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shu-Qun Cheng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China.
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Coffman-D’Annibale K, Xie C, Hrones DM, Ghabra S, Greten TF, Monge C. The current landscape of therapies for hepatocellular carcinoma. Carcinogenesis 2023; 44:537-548. [PMID: 37428789 PMCID: PMC10588973 DOI: 10.1093/carcin/bgad052] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/22/2023] [Accepted: 07/07/2023] [Indexed: 07/12/2023] Open
Abstract
Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total deaths from all cancer types (1). This disease disproportionately affects those in countries with low or medium Human Development Index scores in Eastern Asia, South-Eastern Asia, and Northern and Western Africa (2). Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often develops in the background of chronic liver disease, caused by hepatitis B or C virus, non-alcoholic steatohepatitis (NASH), or other diseases that cause cirrhosis. Prognosis can vary dramatically based on number, size, and location of tumors. Hepatic synthetic dysfunction and performance status (PS) also impact survival. The Barcelona Clinic Liver Cancer (BCLC) staging system best accounts for these variations, providing a reliable prognostic stratification. Therapeutic considerations of this complex disease necessitate a multidisciplinary approach and can range from curative-intent surgical resection, liver transplantation or image-guided ablation to more complex liver-directed therapies like transarterial chemoembolization (TACE) and systemic therapy. Recent advances in the understanding of the tumor biology and microenvironment have brought new advances and approvals for systemic therapeutic agents, often utilizing immunotherapy or VEGF-targeted agents to modulate the immune response. This review will discuss the current landscape in the treatments available for early, intermediate, and advanced stage HCC.
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Affiliation(s)
- Kelley Coffman-D’Annibale
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
| | - Changqing Xie
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
| | - Donna M Hrones
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
| | - Shadin Ghabra
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
| | - Tim F Greten
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
- National Cancer Institute, NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA
| | - Cecilia Monge
- National Cancer Institute, Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, Bethesda, MD, USA
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Wang S, Zhou Y, Yu R, Ling J, Li B, Yang C, Cheng Z, Qian R, Lin Z, Yu C, Zheng J, Zheng X, Jia Q, Wu W, Wu Q, Chen M, Yuan S, Dong W, Shi Y, Jansen R, Yang C, Hao Y, Yao M, Qin W, Jin H. Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2. JHEP Rep 2023; 5:100843. [PMID: 37675273 PMCID: PMC10477690 DOI: 10.1016/j.jhepr.2023.100843] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 06/02/2023] [Accepted: 06/26/2023] [Indexed: 09/08/2023] Open
Abstract
Background & Aims Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.
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Affiliation(s)
- Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangyang Zhou
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruobing Yu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Ling
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Botai Li
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuoan Cheng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruolan Qian
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhang Lin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengtao Yu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingling Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Jia
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiangxin Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengnuo Chen
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Yaoping Shi
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Robin Jansen
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co. Ltd., Nanjing, China
| | - Yujun Hao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Yao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Motomura K, Kuwano A, Tanaka K, Koga Y, Masumoto A, Yada M. Potential Predictive Biomarkers of Systemic Drug Therapy for Hepatocellular Carcinoma: Anticipated Usefulness in Clinical Practice. Cancers (Basel) 2023; 15:4345. [PMID: 37686621 PMCID: PMC10486942 DOI: 10.3390/cancers15174345] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation.
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Affiliation(s)
- Kenta Motomura
- Department of Hepatology, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505, Japan; (A.K.); (K.T.); (Y.K.); (A.M.); (M.Y.)
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Coffin P, He A. Hepatocellular Carcinoma: Past and Present Challenges and Progress in Molecular Classification and Precision Oncology. Int J Mol Sci 2023; 24:13274. [PMID: 37686079 PMCID: PMC10487618 DOI: 10.3390/ijms241713274] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive.
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Affiliation(s)
- Philip Coffin
- MedStar Georgetown University Hospital, Lombardi Cancer Center, 3800 Reservoir Rd NW, Washington, DC 20007, USA;
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Mir SA, Dar A, Alshehri SA, Wahab S, Hamid L, Almoyad MAA, Ali T, Bader GN. Exploring the mTOR Signalling Pathway and Its Inhibitory Scope in Cancer. Pharmaceuticals (Basel) 2023; 16:1004. [PMID: 37513916 PMCID: PMC10384750 DOI: 10.3390/ph16071004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cellular growth, development, survival, and metabolism through integration of diverse extracellular and intracellular stimuli. Additionally, mTOR is involved in interplay of signalling pathways that regulate apoptosis and autophagy. In cells, mTOR is assembled into two complexes, mTORC1 and mTORC2. While mTORC1 is regulated by energy consumption, protein intake, mechanical stimuli, and growth factors, mTORC2 is regulated by insulin-like growth factor-1 receptor (IGF-1R), and epidermal growth factor receptor (EGFR). mTOR signalling pathways are considered the hallmark in cancer due to their dysregulation in approximately 70% of cancers. Through downstream regulators, ribosomal protein S6 kinase β-1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), mTORC1 influences various anabolic and catabolic processes in the cell. In recent years, several mTOR inhibitors have been developed with the aim of treating different cancers. In this review, we will explore the current developments in the mTOR signalling pathway and its importance for being targeted by various inhibitors in anti-cancer therapeutics.
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Affiliation(s)
- Suhail Ahmad Mir
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ashraf Dar
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Saad Ali Alshehri
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Laraibah Hamid
- Department of Zoology, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Mohammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, Abha 61412, Saudi Arabia
| | - Tabasum Ali
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
| | - Ghulam Nabi Bader
- Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Jammu and Kashmir, India
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Singal AG, Kudo M, Bruix J. Breakthroughs in Hepatocellular Carcinoma Therapies. Clin Gastroenterol Hepatol 2023; 21:2135-2149. [PMID: 36813012 PMCID: PMC10293061 DOI: 10.1016/j.cgh.2023.01.039] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/22/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023]
Abstract
Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka Japan.
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clinic, University of Barcelona, Barcelona, Spain.
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Fujinuma S, Nakatsumi H, Shimizu H, Sugiyama S, Harada A, Goya T, Tanaka M, Kohjima M, Takahashi M, Izumi Y, Yagi M, Kang D, Kaneko M, Shigeta M, Bamba T, Ohkawa Y, Nakayama KI. FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation. Cell Rep 2023; 42:112530. [PMID: 37209098 DOI: 10.1016/j.celrep.2023.112530] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/14/2023] [Accepted: 05/02/2023] [Indexed: 05/22/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.
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Affiliation(s)
- Shun Fujinuma
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Hirokazu Nakatsumi
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Hideyuki Shimizu
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Shigeaki Sugiyama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Akihito Harada
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Takeshi Goya
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatomo Takahashi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Mikako Yagi
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka, Japan; Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Dongchon Kang
- Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka, Japan
| | - Mari Kaneko
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Mayo Shigeta
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yasuyuki Ohkawa
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
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44
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1407-1424. [DOI: 10.3748/wjg.v29.i10.1407] [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] [Indexed: 03/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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45
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1551-1568. [PMID: 36970588 PMCID: PMC10037251 DOI: 10.3748/wjg.v29.i10.1551] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/08/2023] [Accepted: 02/22/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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Farasati Far B, Rabie D, Hemati P, Fooladpanjeh P, Faal Hamedanchi N, Broomand Lomer N, Karimi Rouzbahani A, Naimi-Jamal MR. Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy. LIVERS 2023; 3:121-160. [DOI: 10.3390/livers3010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran 1684613114, Iran
| | - Dorsa Rabie
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parisa Hemati
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parastoo Fooladpanjeh
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 193951495, Iran
| | - Nima Broomand Lomer
- Faculty of Medicine, Guilan University of Medical Sciences, Rasht 4314637758, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
- USERN Office, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
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Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:1-120. [PMID: 37384024 PMCID: PMC10202234 DOI: 10.17998/jlc.2022.11.07] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 06/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the fourth most common cancer among men in South Korea, where the prevalence of chronic hepatitis B infection is high in middle and old age. The current practice guidelines will provide useful and sensible advice for the clinical management of patients with HCC. A total of 49 experts in the fields of hepatology, oncology, surgery, radiology, and radiation oncology from the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2018 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions. These guidelines provide useful information and direction for all clinicians, trainees, and researchers in the diagnosis and treatment of HCC.
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Affiliation(s)
- Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea
- Corresponding author: KLCA-NCC Korea Practice Guideline Revision Committee (KPGRC) (Committee Chair: Joong-Won Park) Center for Liver and Pancreatobiliary Cancer, Division of Gastroenterology, Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel. +82-31-920-1605, Fax: +82-31-920-1520, E-mail:
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48
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Bracchiglione J, Rodríguez-Grijalva G, Requeijo C, Santero M, Salazar J, Salas-Gama K, Meade AG, Antequera A, Auladell-Rispau A, Quintana MJ, Solà I, Urrútia G, Acosta-Dighero R, Bonfill Cosp X. Systemic Oncological Treatments versus Supportive Care for Patients with Advanced Hepatobiliary Cancers: An Overview of Systematic Reviews. Cancers (Basel) 2023; 15:cancers15030766. [PMID: 36765723 PMCID: PMC9913533 DOI: 10.3390/cancers15030766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The trade-off between systemic oncological treatments (SOTs) and UPSC in patients with primary advanced hepatobiliary cancers (HBCs) is not clear in terms of patient-centred outcomes beyond survival. This overview aims to assess the effectiveness of SOTs (chemotherapy, immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs. METHODS We searched for systematic reviews (SRs) in PubMed, EMBASE, the Cochrane Library, Epistemonikos and PROSPERO. Two authors assessed eligibility independently and performed data extraction. We estimated the quality of SRs and the overlap of primary studies, performed de novo meta-analyses and assessed the certainty of evidence for each outcome. RESULTS We included 18 SRs, most of which were of low quality and highly overlapped. For advanced hepatocellular carcinoma, SOTs showed better overall survival (HR = 0.62, 95% CI 0.55-0.77, high certainty for first-line therapy; HR = 0.85, 95% CI 0.79-0.92, moderate certainty for second-line therapy) with higher toxicity (RR = 1.18, 95% CI 0.87-1.60, very low certainty for first-line therapy; RR = 1.58, 95% CI 1.28-1.96, low certainty for second-line therapy). Survival was also better for SOTs in advanced gallbladder cancer. No outcomes beyond survival and toxicity could be meta-analysed. CONCLUSION SOTs in advanced HBCs tend to improve survival at the expense of greater toxicity. Future research should inform other patient-important outcomes to guide clinical decision making.
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Affiliation(s)
- Javier Bracchiglione
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar 46383, Chile
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
| | - Gerardo Rodríguez-Grijalva
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Carolina Requeijo
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Correspondence:
| | - Marilina Santero
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Josefina Salazar
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Karla Salas-Gama
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Quality, Process and Innovation Direction, Valld’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Adriana-Gabriela Meade
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Alba Antequera
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - Ariadna Auladell-Rispau
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
| | - María Jesús Quintana
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Ivan Solà
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Gerard Urrútia
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Roberto Acosta-Dighero
- Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar 46383, Chile
| | - Xavier Bonfill Cosp
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
- Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
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Ishido S, Tsuchiya K, Kano Y, Yasui Y, Takaura K, Uchihara N, Suzuki K, Tanaka Y, Miyamoto H, Yamada M, Matsumoto H, Nobusawa T, Keitoku T, Tanaka S, Maeyashiki C, Tamaki N, Takahashi Y, Nakanishi H, Sakurai U, Asahina Y, Okamoto R, Kurosaki M, Izumi N. Clinical Utility of Comprehensive Genomic Profiling in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15030719. [PMID: 36765676 PMCID: PMC9913078 DOI: 10.3390/cancers15030719] [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: 11/22/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
The molecular mechanism of hepatocellular carcinoma (HCC) is partially demonstrated. Moreover, in the patients receiving multiple molecular-targeted therapies, the gene alternations are still unknown. Six molecular-targeted therapies of unresectable HCC (uHCC) and comprehensive genomic profiling (CGP) have been approved in clinical practice. Hence, the utility of CGP in patients with uHCC treated with multiple molecular-targeted agents is investigated. The data of the patients with uHCC who received CGP tests were collected, retrospectively, between February 2021 and May 2022. Gene alterations detected by foundation testing, excluding variants of unknown significance, were reported in all nine patients. The samples for CGP were derived from liver tumor biopsy (n = 2), surgical specimens of bone metastases (n = 2), and blood (n = 5). The median number of systemic therapies was four. Seven patients were candidates eligible for clinical trials. One patient with a high tumor mutation burden (TMB) could receive pembrolizumab after CGP. This study presented genomic alternations after receiving multiple molecular-targeted therapies. However, further investigation needs to be conducted to develop personalized therapies and invent newer agents for treating HCC.
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Affiliation(s)
- Shun Ishido
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Yoshihito Kano
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Clinical Oncology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Naoki Uchihara
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Keito Suzuki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Yuki Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Haruka Miyamoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Michiko Yamada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Hiroaki Matsumoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Tsubasa Nobusawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Taisei Keitoku
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Shohei Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Urara Sakurai
- Department of Pathology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Correspondence: (M.K.); (N.I.); Tel.: +81-422-32-3111 (M.K. & N.I.); Fax: +81-422-32-9551 (M.K. & N.I.)
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo 180-8610, Japan
- Correspondence: (M.K.); (N.I.); Tel.: +81-422-32-3111 (M.K. & N.I.); Fax: +81-422-32-9551 (M.K. & N.I.)
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Arai J, Otoyama Y, Nozawa H, Kato N, Yoshida H. The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review. Oncogene 2023; 42:549-558. [PMID: 36572816 PMCID: PMC9937921 DOI: 10.1038/s41388-022-02583-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/27/2022]
Abstract
Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.
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Affiliation(s)
- Jun Arai
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
| | - Yumi Otoyama
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hisako Nozawa
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Naoya Kato
- grid.136304.30000 0004 0370 1101Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hitoshi Yoshida
- grid.410714.70000 0000 8864 3422Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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