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Inoue FSR, Concato-Lopes VM, Bortoleti BTDS, Cruz EMS, Detoni MB, Tomiotto-Pellissier F, Gonçalves-Lens MD, Morais-Valentim JMBD, Machado RRB, Santiago-Silva KM, Bispo MDLF, Schirmann JG, Barbosa-Dekker AM, Dekker RFH, Assis MCTD, Conchon-Costa I, Mantovani MS, Lazarin-Bidóia D, Panis C, Pavanelli WR. 3,3',5,5'-Tetramethoxybiphenyl-4,4'-diol exerts a cytotoxic effect on hepatocellular carcinoma cell lines by inducing morphological and ultrastructural alterations, G2/M cell cycle arrest and death by apoptosis via CDK1 interaction. Biomed Pharmacother 2025; 187:118082. [PMID: 40280030 DOI: 10.1016/j.biopha.2025.118082] [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: 10/01/2024] [Revised: 04/14/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with frequent recurrence and chemoresistance, underscoring the need for new treatment strategies. 3,3',5,5'-Tetramethoxybiphenyl-4,4'-diol (TMBP) showed cytotoxicity against lung cancer cell lines without harming normal cells. Thus, we investigated the antitumoral effect of TMBP on HCC cell lines, HuH7.5 (p53-mutant) and HepG2/C3A (p53-wild type). Cells were treated with TMBP (12.5-150 µM) for 24 and 48 h, and metabolic cellular activity (MTT) were used to determine the 50 % inhibitory concentration (IC50) values. TMBP cytotoxicity were assessed by Trypan blue assay, scanning and transmission electron microscopy. Cell migration (wound healing), total ROS (H2DCFDA), mitochondrial dysfunction (TMRE), lipid droplets (Nile Red), and autophagic vacuoles (MDC) were assessed. Flow cytometry characterized cell cycle distribution and cell death. Caspase 3/7 activity and CASP3 expression confirmed apoptosis. Molecular docking and gene expression analysis validated TMBP-CDK1 interaction. TMBP reduced cell viability, with IC50 values of 68 and 55 µM (HuH7.5) and 50 and 42 µM (HepG2/C3A) at 24 and 48 h. TMBP induced severe morphological alterations, impaired migration, increased ROS, mitochondrial dysfunction, increased lipid droplets and autophagic vacuoles. TMBP also led to G2/M arrest and apoptosis, likely via CDK1 inhibition through hydrogen bonding at Tyr15. These findings highlight TMBP as a promising therapeutic candidate targeting CDK1 in HCC.
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Affiliation(s)
- Fabricio Seidy Ribeiro Inoue
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil.
| | - Virginia Marcia Concato-Lopes
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Bruna Taciane da Silva Bortoleti
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Ellen Mayara Souza Cruz
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Mariana Barbosa Detoni
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Fernanda Tomiotto-Pellissier
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil; Department of Medical Pathology, Federal University of Paraná, Curitiba, PR, Brazil
| | - Manoela Daiele Gonçalves-Lens
- Laboratory of Biotransformation and Phytochemical, Department of Chemistry, State University of Londrina, Londrina, PR, Brazil
| | - Juliana Maria Bitencourt de Morais-Valentim
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Rayanne Regina Beltrame Machado
- Laboratory of Technological Innovation in the Development of Drugs and Cosmetics, Department of Basic Health Sciences, State University of Maringá, Maringá, PR, Brazil
| | - Kaio Maciel Santiago-Silva
- Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Department of Chemistry, State University of Londrina, Londrina, PR, Brazil
| | - Marcelle de Lima Ferreira Bispo
- Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Department of Chemistry, State University of Londrina, Londrina, PR, Brazil
| | - Jéseka Gabriela Schirmann
- Laboratory of Research of Bioactive Molecules, Department of Chemistry, State University of Londrina, Londrina, PR, Brazil
| | - Aneli M Barbosa-Dekker
- Laboratory of Research of Bioactive Molecules, Department of Chemistry, State University of Londrina, Londrina, PR, Brazil; Beta-Glucan Produtos Farmoquímicos-EIRELI, Lote 24A - Bloco Zircônia, Universidade Tecnológica Federal do Paraná, Londrina, PR CEP: 86036-700, Brazil
| | - Robert F H Dekker
- Beta-Glucan Produtos Farmoquímicos-EIRELI, Lote 24A - Bloco Zircônia, Universidade Tecnológica Federal do Paraná, Londrina, PR CEP: 86036-700, Brazil
| | | | - Ivete Conchon-Costa
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
| | - Mário Sérgio Mantovani
- Laboratory of Toxicological Genetics, Department of General Biology, State University of Londrina, Londrina, PR, Brazil
| | - Danielle Lazarin-Bidóia
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil; Laboratory of Technological Innovation in the Development of Drugs and Cosmetics, Department of Basic Health Sciences, State University of Maringá, Maringá, PR, Brazil
| | - Carolina Panis
- Laboratory of Tumor Biology, Center of Health Sciences, State University of Western Parana, Francisco Beltrão, PR, Brazil
| | - Wander Rogério Pavanelli
- Laboratory of Immunoparasitology of Neglected Diseases and Cancer, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina, PR, Brazil
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Wu Y, Zeng Z, Chen S, Zhou D, Tong G, Du D. Adverse events associated with hepatic arterial infusion chemotherapy and its combination therapies in hepatocellular carcinoma: a systematic review. Front Immunol 2025; 16:1531249. [PMID: 40098973 PMCID: PMC11911461 DOI: 10.3389/fimmu.2025.1531249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Background Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment for unresectable hepatocellular carcinoma (HCC). However, the safety profiles of HAIC and its various combination therapies remain to be systematically evaluated. Methods We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to November 2024. Studies reporting adverse events (AEs) of HAIC monotherapy or combination therapies in HCC were included. The severity and frequency of AEs were analyzed according to different treatment protocols. Results A total of 58 studies (11 prospective, 47 retrospective) were included. HAIC monotherapy demonstrated relatively mild toxicity, primarily affecting hepatobiliary (transaminase elevation 53.2%, hypoalbuminemia 57.2%) and hematological systems (anemia 43.0%, thrombocytopenia 35.2%). HAIC with targeted therapy showed increased adverse events, including characteristic reactions like hand-foot syndrome (48.0%) and hypertension (49.9%). HAIC combined with targeted, and immunotherapy exhibited the highest adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), while HAIC with anti-angiogenic and immunotherapy showed a relatively favorable safety profile. Prospective studies consistently reported higher incidence rates than retrospective studies, suggesting potential underreporting in clinical practice. Conclusions Different HAIC-based regimens exhibit distinct safety profiles requiring individualized management approaches. We propose a comprehensive framework for patient selection, monitoring strategies, and AE management. These recommendations aim to optimize treatment outcomes while minimizing adverse impacts on patient quality of life.
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Affiliation(s)
- Ying Wu
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhenpeng Zeng
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Shuanggang Chen
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- StateKey Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Danyang Zhou
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Gangling Tong
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Duanming Du
- Department of Interventional Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
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3
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Pouyan A, Ghorbanlo M, Eslami M, Jahanshahi M, Ziaei E, Salami A, Mokhtari K, Shahpasand K, Farahani N, Meybodi TE, Entezari M, Taheriazam A, Hushmandi K, Hashemi M. Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies. Mol Cancer 2025; 24:58. [PMID: 40011944 PMCID: PMC11863469 DOI: 10.1186/s12943-025-02267-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.
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Affiliation(s)
- Ashkan Pouyan
- Department of Neurosurgery, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Masoud Ghorbanlo
- Department of Anesthesiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoud Eslami
- Department of Neurosurgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Jahanshahi
- Department of Neurosurgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ehsan Ziaei
- Department of Neurosurgery, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Salami
- Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khatere Mokhtari
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Koorosh Shahpasand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Laboratory Medicine and Pathology, Institute for Translational Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Tohid Emami Meybodi
- Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Functional Neurosurgery Research Center, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Epidemiology, University of Tehran, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Hossain MA. A comprehensive review of targeting RAF kinase in cancer. Eur J Pharmacol 2025; 986:177142. [PMID: 39577552 DOI: 10.1016/j.ejphar.2024.177142] [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: 08/25/2024] [Revised: 11/11/2024] [Accepted: 11/17/2024] [Indexed: 11/24/2024]
Abstract
RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [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: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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Xander NSH, Leeneman B, Dingemans AMC, Fiets WE, de Jong WK, Uyl NEM, Wymenga ANM, Reyners AKL, Uyl-de Groot CA. Using non-randomized trials to assess the clinical benefit of systemic anti-cancer treatments: Viable or not? Eur J Cancer 2024; 209:114262. [PMID: 39111205 DOI: 10.1016/j.ejca.2024.114262] [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: 05/07/2024] [Revised: 07/25/2024] [Accepted: 07/25/2024] [Indexed: 08/25/2024]
Abstract
BACKGROUND The Dutch Committee for the Evaluation of Oncological Agents (cieBOM) assesses the clinical benefit of systemic anti-cancer treatments (SACTs). For SACTs tested in non-randomized trials (NRTs), cieBOM primarily utilizes response-related thresholds as assessment criteria. As sufficiency of NRT-based evidence for benefit assessments is questionable, this study investigated whether and how NRTs can be used to assess the clinical benefit of new SACTs initially appraised by cieBOM based on randomized controlled trials (RCTs). METHODS Using the RCTs underpinning cieBOM recommendations issued between 2015 and 2017, we searched for matching NRTs and applied the NRT-related assessment criteria by cieBOM to them. We then compared the assessment outcomes to the respective RCT-based cieBOM recommendations. Further, we investigated how the assessments would change when applying different response-related thresholds and adding a progression-free survival (PFS) threshold. RESULTS For 13 of the 37 eligible recommendations, a matching NRT was found. Two treatments were assessed positively and six negatively; five treatments were non-assessable. Two positive recommendations matched a positive NRT-based assessment; one matching negative assessment was found, and one treatment could not be assessed based on either trial results. Adding a > 6 months PFS threshold decreased the number of non-assessable NRTs (five to two). CONCLUSIONS Limited publications and inconsistent data reporting hampered the viability of NRTs for clinical benefit assessments of SACTs beyond the scope of rare indications. Further, response-related assessment criteria alone might not fully grasp the clinical benefit of novel SACTs. NRT-based assessments should be considered with caution due to uncertainty of the trial results.
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Affiliation(s)
- N S H Xander
- Department of Health Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands; Erasmus Centre for Health Economics Rotterdam, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands.
| | - B Leeneman
- Department of Health Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands; Erasmus Centre for Health Economics Rotterdam, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands
| | - A-M C Dingemans
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - W E Fiets
- Department of Medical Oncology, Medical Center Leeuwarden, Henri Dunantweg 2, 8934 AD Leeuwarden, the Netherlands
| | - W K de Jong
- Department of Pulmonology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - N E M Uyl
- Department of Health Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands
| | - A N M Wymenga
- Department of Medical Oncology, Medisch Spectrum Twente, Koningsplein 1, 7512 KZ Enschede, the Netherlands
| | - A K L Reyners
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands
| | - C A Uyl-de Groot
- Department of Health Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands; Erasmus Centre for Health Economics Rotterdam, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, the Netherlands
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Poklepovic AS, Gordon SW, Kothadia S, McGuire WP, Thacker LR, Deng X, Tombes MB, Shrader E, Hudson D, Bandyopadhyay D, Ryan AA, Kmieciak M, Smith S, Dent P. A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors. Anticancer Drugs 2024; 35:450-458. [PMID: 38452059 PMCID: PMC11168782 DOI: 10.1097/cad.0000000000001584] [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: 09/14/2023] [Accepted: 01/25/2024] [Indexed: 03/09/2024]
Abstract
The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Paul Dent
- Massey Cancer Center
- Biochemistry, Virginia Commonwealth University, Richmond, Virginia, USA
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Mongiardi MP, Pallini R, D'Alessandris QG, Levi A, Falchetti ML. Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness. Expert Rev Mol Med 2024; 26:e5. [PMID: 38563164 PMCID: PMC11062143 DOI: 10.1017/erm.2024.8] [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: 04/27/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/04/2024]
Abstract
Glioblastoma IDH wild type (GBM) is a very aggressive brain tumour, characterised by an infiltrative growth pattern and by a prominent neoangiogenesis. Its prognosis is unfortunately dismal, and the median overall survival of GBM patients is short (15 months). Clinical management is based on bulk tumour removal and standard chemoradiation with the alkylating drug temozolomide, but the tumour invariably recurs leading to patient's death. Clinical options for GBM patients remained unaltered for almost two decades until the encouraging results obtained by the phase II REGOMA trial allowed the introduction of the multikinase inhibitor regorafenib as a preferred regimen in relapsed GBM treatment by the National Comprehensive Cancer Network (NCCN) 2020 Guideline. Regorafenib, a sorafenib derivative, targets kinases associated with angiogenesis (VEGFR 1-3), as well as oncogenesis (c-KIT, RET, FGFR) and stromal kinases (FGFR, PDGFR-b). It was already approved for metastatic colorectal cancers and hepatocellular carcinomas. The aim of the present review is to focus on both the molecular and clinical knowledge collected in these first three years of regorafenib use in GBM.
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Affiliation(s)
| | - Roberto Pallini
- Department of Neuroscience, Neurosurgery Section, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Andrea Levi
- Institute of Biochemistry and Cell Biology, IBBC-CNR, Monterotondo, Rome, Italy
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9
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Tajiri K, Muraishi N, Murayama A, Hayashi Y, Yasuda I. Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma. Hepatol Res 2024; 54:403-408. [PMID: 37924508 DOI: 10.1111/hepr.13986] [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: 09/19/2023] [Revised: 10/24/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
AIM Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. METHODS Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. RESULTS In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R2 = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation (R2 = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R2 = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation (R2 = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R2 = 0.856, R = 0.925, p = 0.003) as did PFS (R2 = 0.946, R = 0.973, p < 0.001). CONCLUSIONS PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.
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Affiliation(s)
- Kazuto Tajiri
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Nozomu Muraishi
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Aiko Murayama
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Yuka Hayashi
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Ichiro Yasuda
- Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
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10
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De Gaetano V, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:1388. [PMID: 38611066 PMCID: PMC11011056 DOI: 10.3390/cancers16071388] [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: 02/21/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.
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Affiliation(s)
- Valeria De Gaetano
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Maria Pallozzi
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Lucia Cerrito
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Francesco Santopaolo
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Leonardo Stella
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Antonio Gasbarrini
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
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11
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Becht R, Kiełbowski K, Wasilewicz MP. New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow. Int J Mol Sci 2024; 25:1456. [PMID: 38338736 PMCID: PMC10855889 DOI: 10.3390/ijms25031456] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.
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Affiliation(s)
- Rafał Becht
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; (R.B.); (K.K.)
| | - Michał P. Wasilewicz
- Liver Unit, Department of Gastroenterology, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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12
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Yu H, Zhang X, Li J, Wang K, Yin C, Li X, Li L, Shao G, Jin S. Design, Synthesis and Evaluation of a Novel Teoptinib Derivative as an Effective Anti-hepatocellular Carcinoma Agent. Curr Pharm Des 2024; 30:2167-2178. [PMID: 38919077 DOI: 10.2174/0113816128314500240621071306] [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: 03/14/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND & PURPOSE Hepatocellular Carcinoma (HCC) is a type of liver cancer known for its poor prognosis and high mortality. Teoptinib is a highly selective MET inhibitor that has been used in the treatment of liver cancer. Although good progress has been made in clinical treatment, further improvement is still needed. In this study, a series of novel Teoptinib derivatives were synthesized and evaluated as anti-cancer agents for the treatment of liver cancer, and an oral nanodrug delivery system was also explored. METHODS A series of novel Teoptinib derivatives were synthesized, and an oral nanodrug delivery system was also explored. HPLC, high-resolution mass spectrometer and NMR were used to determine the structure and molecular formula of the synthesized compounds. Zeta potential assay was used to access the particle size distribution and zeta potential of the nanoparticles. MTT assay, cell colony formation assay, cell apoptosis inhibition assay, cell scratch assay, and the MHCC-97H xenograft model of nude mice assay were used to evaluate the in vitro and in vivo anti-tumor activity of the synthesized compounds. RESULTS Compound (R)-10 showed the best antitumor activity with 0.010 μM of the IC50 value against MHCC-97H, a human liver cancer cell line with high c-Met expression. The MHCC-97H xenograft model of nude mice assay showed that nano-prodrug of compound (R)-10 exhibited good in vivo activity with 87.67% of the TGI at the dosage of 8 mg/kg. CONCLUSION We designed and synthesized a series of c-Met inhibitors containing different side chains and chiral centers as anti-liver cancer agents. Among them, compound (R)-10 shows a promising effect as a lead molecule for further study in the treatment of liver cancer. The successful incorporation of (R)-10 into a novel oral nanodrug delivery system highlights the importance of effective drug delivery systems for enhanced therapeutic efficacy.
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MESH Headings
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/chemical synthesis
- Animals
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Drug Design
- Mice
- Mice, Nude
- Apoptosis/drug effects
- Cell Proliferation/drug effects
- Drug Screening Assays, Antitumor
- Structure-Activity Relationship
- Molecular Structure
- Dose-Response Relationship, Drug
- Proto-Oncogene Proteins c-met/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/metabolism
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/metabolism
- Mice, Inbred BALB C
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Cell Line, Tumor
- Nanoparticles/chemistry
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Affiliation(s)
- Huijuan Yu
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou 510275, China
| | - Xiaodong Zhang
- School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
| | - Jiayu Li
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou 510275, China
| | - Kaimei Wang
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Changjun Yin
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Xinshu Li
- School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
| | - Lianyun Li
- School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
| | - Guang Shao
- School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
| | - Shaowen Jin
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
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13
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Aasarey R, Yadav K, Kashyap BK, Prabha S, Kumar P, Kumar A, Ruokolainen J, Kesari KK. Role of Immunological Cells in Hepatocellular Carcinoma Disease and Associated Pathways. ACS Pharmacol Transl Sci 2023; 6:1801-1816. [PMID: 38093838 PMCID: PMC10714437 DOI: 10.1021/acsptsci.3c00216] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 03/28/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the predominant causes of cancer-related mortality across the globe. It is attributed to obesity, excessive alcohol consumption, smoking, and infection by the hepatitis virus. Early diagnosis of HCC is essential, and local treatments such as surgical excision and percutaneous ablation are effective. Palliative systemic therapy, primarily with the tyrosine kinase inhibitor Sorafenib, is used in advanced cases. However, the prognosis for advanced HCC remains poor. This Review additionally describes the pathophysiological mechanisms of HCC, which include aberrant molecular signaling, genomic instability, persistent inflammation, and the paradoxical position of the immune system in promoting and suppressing HCC. The paper concludes by discussing the growing body of research on the relationship between mitochondria and HCC, suggesting that mitochondrial dysfunction may contribute to the progression of HCC. This Review focuses on immunological interactions between different mechanisms of HCC progression, including obesity, viral infection, and alcohol consumption.
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Affiliation(s)
- Ram Aasarey
- Department
of Laboratory Medicine, All India Institute
of Medical Science, New Delhi-11029, India
| | - Kajal Yadav
- Department
of Biotechnology, All India Institute of
Medical Science, New Delhi-11029, India
| | - Brijendra Kumar Kashyap
- Department
of Biotechnology Engineering, Institute of Engineering and Technology, Bundelkhand University, Jhansi-284128, Uttar Pradesh, India
| | - Sarit Prabha
- Department
of Biological Science and Engineering, Maulana
Azad National Institute of Technology, Bhopal-462003, Madhya Pradesh,India
| | - Pramod Kumar
- Indian
Council of Medical Research, National Institute
of Cancer Prevention and Research (NICPR), l-7, Sector-39, Noida-201301, National Capital Region, India
| | - Anil Kumar
- Department
of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Karmre, Kanke-835222, Ranchi, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, FI-00076 Espoo, Finland
- Research
and Development Cell, Lovely Professional
University, Phagwara-144411, Punjab, India
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14
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Ye W, Wang Z, Lv X, Yin H, Jiang L, Wang Z, Liu Y. Potential risk of drug-drug interactions of ponatinib via inhibition against human UDP-glucuronosyltransferases. Toxicol In Vitro 2023; 92:105664. [PMID: 37597759 DOI: 10.1016/j.tiv.2023.105664] [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: 03/15/2023] [Revised: 07/10/2023] [Accepted: 08/16/2023] [Indexed: 08/21/2023]
Abstract
Ponatinib is an efficient oral tyrosine kinase inhibitor (TKI) for T315I-positive Ph + ALL and T315I-positive chronic myeloid leukemia (CML) or BCR-ABL when no other TKIs can be prescribed. In this research, we evaluated the inhibitory effects of ponatinib on human recombinant UDP-glucuronosyltransferases (UGTs) and predicted the magnitude of potential drug-drug interaction (DDI) risk of co-treatment with ponatinib and UGTs substrates by using in vitro-in vivo extrapolation (IVIVE) method. Our study presented that ponatinib showed a broad-spectrum inhibition against UGTs. Particularly, ponatinib exhibited potent inhibitory effects towards UGT1A7, UGT1A1, and UGT1A9 with IC50 values of 0.37, 0.41, and 0.89 μM, respectively, which might lead to clinically significant DDI.
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Affiliation(s)
- Weiyi Ye
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Zhen Wang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Xin Lv
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Hang Yin
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Lili Jiang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China
| | - Zhe Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Yong Liu
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China.
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15
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Suresh D, Srinivas AN, Prashant A, Harikumar KB, Kumar DP. Therapeutic options in hepatocellular carcinoma: a comprehensive review. Clin Exp Med 2023; 23:1901-1916. [PMID: 36780119 DOI: 10.1007/s10238-023-01014-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/27/2023] [Indexed: 02/14/2023]
Abstract
Hepatocellular carcinoma (HCC) is a chronic liver disease that is highly fatal if not detected and treated early. The incidence and death rate of HCC have been increasing in recent decades despite the measures taken for preventive screening and effective diagnostic and treatment strategies. The pathophysiology of HCC is multifactorial and highly complex owing to its molecular and immune heterogeneity, and thus the gap in knowledge still precludes making choices between viable therapeutic options and also the development of effective regimens. The treatment of HCC demands multidisciplinary approaches and primarily depends on tumor stage, hepatic functional reserve, and response to treatment by patients. Although curative treatments are limited but critical in the early stages of cancer, there are numerous palliative treatments available for patients with intermediate and advanced-stage HCC. In recent times, the use of combination therapy has succeeded over the use of monotherapy in the treatment of HCC by achieving effective tumor suppression, increasing survival rate, decreasing toxicity, and also aiding in overcoming drug resistance. This work focuses on reviewing the current and emerging treatment strategies for HCC.
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Affiliation(s)
- Diwakar Suresh
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Akshatha N Srinivas
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Akila Prashant
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, India
| | - Divya P Kumar
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India.
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16
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Wang Y, Zhao Y, Li M, Hou H, Jian Z, Li W, Li P, Ma F, Liu M, Liu H, Xue H. Conversion of primary liver cancer after targeted therapy for liver cancer combined with AFP-targeted CAR T-cell therapy: a case report. Front Immunol 2023; 14:1180001. [PMID: 37256142 PMCID: PMC10225497 DOI: 10.3389/fimmu.2023.1180001] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/02/2023] [Indexed: 06/01/2023] Open
Abstract
Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.
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17
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Pan Y, Zhu X, Liu J, Zhong J, Zhang W, Shen S, Jin R, Liu H, Ye F, Hu K, Xu D, Zhang Y, Chen Z, Xing B, Zhou L, Chen Y, Zeng Y, Liang X, Kuang M, Song T, Xiang B, Wang K, Sun H, Xu L, China Liver Cancer Study Group Young Investigators (CLEAP). Systemic therapy with or without transcatheter intra-arterial therapies for unresectable hepatocellular carcinoma: a real-world, multi-center study. Front Immunol 2023; 14:1138355. [PMID: 37180173 PMCID: PMC10169746 DOI: 10.3389/fimmu.2023.1138355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Systemic therapy is the standard care of unresectable hepatocellular carcinoma (uHCC), while transcatheter intra-arterial therapies (TRITs) were also widely applied to uHCC patients in Chinese practice. However, the benefit of additional TRIT in these patients is unclear. This study investigated the survival benefit of concurrent TRIT and systemic therapy used as first-line treatment for patients with uHCC. METHODS This real-world, multi-center retrospective study included consecutive patients treated at 11 centers accross China between September 2018 and April 2022. Eligible patients had uHCC of China liver cancer stages IIb to IIIb (Barcelona clinic liver cancer B or C stage), and received first-line systemic therapy with or without concurrent TRIT. Of 289 patients included, 146 received combination therapy and 143 received systemic therapy alone. The overall survival (OS), as primary outcomes, was compared between patients who received systemic therapy plus TRIT (combination group) or systemic therapy alone (systemic-only group) using survival analysis and Cox regression. Imbalances in baseline clinical features between the two groups were adjusted through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Moreover, subgroup analysis was conducted based on the different tumor characteristics of enrolled uHCC patients. RESULTS The median OS was significantly longer in the combination group than the systemic-only group before adjustment [not reached vs. 23.9 months; hazard ratio (HR), 0.561; 95% confidence interval (CI), 0.366 to 0.861; P = 0.008], after PSM (HR, 0.612; 95% CI, 0.390 to 0.958; P = 0.031) and after IPTW (HR, 0.539; 95% CI, 0.116 to 0.961; P = 0.008). Subgroup analyses suggested the benefit of combining TRIT with systemic therapy was greatest in patients with liver tumors exceeding the up-to-seven criteria, with an absence of extrahepatic metastasis, or with alfa-fetoprotein ≥ 400 ng/ml. CONCLUSION Concurrent TRIT with systemic therapy was associated with improved survival compared with systemic therapy alone as first-line treatment for uHCC, especially for patients with high-intrahepatic tumor load and no extrahepatic metastasis.
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Affiliation(s)
- Yangxun Pan
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaodong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianwei Liu
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jianhong Zhong
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Nanning, China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Shunli Shen
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
| | - Renan Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Institute of Minimally Invasive Surgery, Zhejiang University, Hangzhou, China
| | - Hongzhi Liu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, China
| | - Feng Ye
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Da Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhong Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing, China
| | - Ledu Zhou
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yongjun Chen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongyi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Institute of Minimally Invasive Surgery, Zhejiang University, Hangzhou, China
| | - Ming Kuang
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Guangxi Medical University, Nanning, China
| | - Kui Wang
- Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Huichuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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18
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Yang J, Zeng L, Chen R, Zheng S, Zhou Y, Chen R. Characterization of heterogeneous metabolism in hepatocellular carcinoma identifies new therapeutic target and treatment strategy. Front Immunol 2023; 14:1076587. [PMID: 37006288 PMCID: PMC10060979 DOI: 10.3389/fimmu.2023.1076587] [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: 10/21/2022] [Accepted: 02/08/2023] [Indexed: 03/18/2023] Open
Abstract
BackgroundMetabolic reprogramming is a well-known hallmark of cancer. Systematical identification of clinically relevant metabolic subtypes of Hepatocellular carcinoma (HCC) is critical to understand tumor heterogeneity and develop efficient treatment strategies.MethodsWe performed an integrative analysis of genomic, transcriptomic, and clinical data from an HCC patient cohort in The Cancer Genome Atlas (TCGA).ResultsFour metabolic subtypes were defined: mHCC1, mHHC2, mHCC3, and mHCC4. These subtypes had distinct differences in mutations profiles, activities of metabolic pathways, prognostic metabolism genes, and immune features. The mHCC1 was associated with poorest outcome and was characterized by extensive metabolic alterations, abundant immune infiltration, and increased expression of immunosuppressive checkpoints. The mHHC2 displayed lowest metabolic alteration level and was associated with most significant improvement in overall survival in response to high CD8+ T cell infiltration. The mHHC3 was a “cold-tumor” with low immune infiltration and few metabolic alterations. The mHCC4 presented a medium degree of metabolic alteration and high CTNNB1 mutation rate. Based on our HCC classification and in vitro study, we identified palmitoyl-protein thioesterase 1 (PPT1) was a specific prognostic gene and therapeutic target for mHCC1.ConclusionOur study highlighted mechanistic differences among metabolic subtypes and identified potential therapeutic targets for subtype-specific treatment strategies targeting unique metabolic vulnerabilities. The immune heterogeneities across metabolic subtypes may help further clarify the association between metabolism and immune environment and guide the development of novel strategies through targeting both unique metabolic vulnerabilities and immunosuppressive triggers.
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Affiliation(s)
- Jiabin Yang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Liangtang Zeng
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ruiwan Chen
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shangyou Zheng
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yu Zhou
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- *Correspondence: Rufu Chen, ; Yu Zhou,
| | - Rufu Chen
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Department of Pancreatic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- *Correspondence: Rufu Chen, ; Yu Zhou,
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19
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Kanogawa N, Ogasawara S, Maruta S, Iino Y, Obu M, Ishino T, Ogawa K, Yumita S, Iwanaga T, Unozawa H, Nakagawa M, Fujiwara K, Sakuma T, Fujita N, Kojima R, Kanzaki H, Koroki K, Kobayashi K, Inoue M, Kiyono S, Nakamura M, Kondo T, Saito T, Nakagawa R, Nakamoto S, Muroyama R, Chiba T, Itobayashi E, Koma Y, Azemoto R, Kato J, Kato N. Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma. BMC Gastroenterol 2023; 23:70. [PMID: 36906542 PMCID: PMC10007811 DOI: 10.1186/s12876-023-02674-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 02/13/2023] [Indexed: 03/13/2023] Open
Abstract
PURPOSE Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.
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Affiliation(s)
- Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.
| | - Susumu Maruta
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Yotaro Iino
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Masamichi Obu
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Sae Yumita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hidemi Unozawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoto Fujita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Yoshihiro Koma
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Ryosaku Azemoto
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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20
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Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma. Biomed Pharmacother 2023; 159:114254. [PMID: 36669362 DOI: 10.1016/j.biopha.2023.114254] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/09/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-β1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-β1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-β1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-β1. In conclusion, IFN-γ induced TGF-β1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.
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21
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Kumar S, Pandey AK. Potential Molecular Targeted Therapy for Unresectable Hepatocellular Carcinoma. Curr Oncol 2023; 30:1363-1380. [PMID: 36826066 PMCID: PMC9955633 DOI: 10.3390/curroncol30020105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers, representing a serious worldwide health concern. The recurrence incidence of hepatocellular carcinoma (HCC) following surgery or ablation is as high as 70%. Thus, the clinical applicability of standard surgery and other locoregional therapy to improve the outcomes of advanced HCC is restricted and far from ideal. The registered trials did not identify a treatment that prolonged recurrence-free survival, the primary outcome of the majority of research. Several investigator-initiated trials have demonstrated that various treatments extend patients' recurrence-free or overall survival after curative therapies. In the past decade, targeted therapy has made significant strides in the treatment of advanced HCC. These targeted medicines produce antitumour effects via specific signals, such as anti-angiogenesis or advancement of the cell cycle. As a typical systemic treatment option, it significantly improves the prognosis of this fatal disease. In addition, the combination of targeted therapy with an immune checkpoint inhibitor is redefining the paradigm of advanced HCC treatment. In this review, we focused on the role of approved targeted medicines and potential therapeutic targets in unresectable HCC.
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Affiliation(s)
- Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Guddha, Bathinda 151401, Punjab, India
| | - Abhay Kumar Pandey
- Department of Biochemistry, University of Allahabad, University Road, Prayagraj 211002, Uttar Pradesh, India
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22
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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23
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Peng W, Jiang X, Zhang W, Hu J, Zhang Y, Zhang L. A radiomics-based model can predict recurrence-free survival of hepatocellular carcinoma after curative ablation. Asian J Surg 2022:S1015-9584(22)01409-9. [DOI: 10.1016/j.asjsur.2022.09.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/16/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
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Andrzejewska M, Czarny J, Derwich K. Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors. Cancers (Basel) 2022; 14:4989. [PMID: 36291774 PMCID: PMC9599787 DOI: 10.3390/cancers14204989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022] Open
Abstract
Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs biologically from adult-type diseases presenting mutations of KIT and PDGFR genes. In this population, more frequent is the wild-type GIST possessing SDH, TRK, RAS, NF1 mutations, among others. Both tumor types require individualized treatment with kinase inhibitors that are still being tested in the pediatric population due to the different neoplasm biology. We review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease that enables the definition of possible resistance. Emerging treatment with kinase inhibitors that could serve as targeted therapy is discussed, especially with multikinase inhibitors of higher generation, the effectiveness of which has already been confirmed in the adult population.
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Affiliation(s)
- Marta Andrzejewska
- Faculty of Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland or
| | - Jakub Czarny
- Faculty of Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland or
| | - Katarzyna Derwich
- Department of Pediatric Oncology, Hematology and Transplantology, Institute of Pediatrics, Poznan University of Medical Sciences, 60-355 Poznan, Poland
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25
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Bartos A, Iancu I, Ciobanu L, Onaciu A, Moldovan C, Moldovan A, Moldovan RC, Tigu AB, Stiufiuc GF, Toma V, Iancu C, Al Hajjar N, Stiufiuc RI. Hybrid Lipid Nanoformulations for Hepatoma Therapy: Sorafenib Loaded Nanoliposomes-A Preliminary Study. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:2833. [PMID: 36014698 PMCID: PMC9414144 DOI: 10.3390/nano12162833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 06/15/2023]
Abstract
Sorafenib is a multikinase inhibitor that has received increasing attention due to its high efficacy in hepatocellular carcinoma treatment. However, its poor pharmacokinetic properties (limited water solubility, rapid elimination, and metabolism) still represent major bottlenecks that need to be overcome in order to improve Sorafenib's clinical application. In this paper, we propose a nanotechnology-based hybrid formulation that has the potential to overcome these challenges: sorafenib-loaded nanoliposomes. Sorafenib molecules have been incorporated into the hydrophobic lipidic bilayer during the synthesis process of nanoliposomes using an original procedure developed in our laboratory and, to the best of our knowledge, this is the first paper reporting this type of analysis. The liposomal hybrid formulations have been characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA) that provided useful information concerning their shape, size, zeta-potential, and concentration. The therapeutic efficacy of the nanohybrids has been evaluated on a normal cell line (LX2) and two hepatocarcinoma cell lines, SK-HEP-1 and HepG2, respectively.
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Affiliation(s)
- Adrian Bartos
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- Department of Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Ioana Iancu
- Department of Surgery, Medicover Hospital, 407062 Cluj-Napoca, Romania
| | - Lidia Ciobanu
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Anca Onaciu
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
- Department of Pharmaceutical Physics-Biophysics, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Cristian Moldovan
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
- Department of Pharmaceutical Physics-Biophysics, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Alin Moldovan
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Radu Cristian Moldovan
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Adrian Bogdan Tigu
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | | | - Valentin Toma
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Cornel Iancu
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- Department of Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Rares Ionut Stiufiuc
- MedFuture—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
- Department of Pharmaceutical Physics-Biophysics, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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26
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Nour MA, Kheradmand F, Rasmi Y, Baradaran B. Alpha7 nicotinic acetylcholine receptor expression in Sorafenib-resistant Hepatocellular carcinoma cells. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:165. [PMID: 35972579 DOI: 10.1007/s12032-022-01745-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/04/2022] [Indexed: 11/28/2022]
Abstract
Hepatocellular carcinoma (HCC), the most prevalent kind of liver cancer, remains one of the world's main causes of death. The alpha7 nicotinic acetylcholine receptor (α7nAchR) has been recognized to be overexpressed in malignancies and chemoresistance. Since little is known about the role of α7nAchR expression in drug-resistant cells, this study was designed to investigate the effect of α7nAchR suppression in combination with Sorafenib (SOR) on SOR-resistant HCC cells. First, SOR-resistant HCC cells were generated. To suppress the expression of α7nAchR, cells were treated with SOR following siRNA transfection. qRT-PCR was used to examine the expression of α7nAchR and apoptotic genes by evaluating the IC50 of SOR and the combination of α7nAchR siRNA and SOR on the survival of resistant cells. Moreover, apoptosis, autophagy, and cell cycle analysis for resistant HCC cells were performed using flow cytometry. Cell migration and colony formation assays were also used for further confirmation. Our results suggest that inhibiting α7nAchR can lead resistant HCC cells to become sensitive. Furthermore, when siRNA and SOR were treated together, HCC-resistant cells showed a considerable reduction in α7nAchR mRNA gene expression. In addition, when α7nAchR was downregulated in combination with SOR, migration and colony formation were inhibited. Apoptosis was triggered by modulating the expression of apoptotic target genes, and cell cycle arrest was observed in the G2-M and subG1 phases. Overexpression of α7nAchR in SOR-resistant HCC cells suggests that it might be a therapeutic target for HCC cell resistance therapy.
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Affiliation(s)
- Mina Afrashteh Nour
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
| | - Yousef Rasmi
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. .,Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, 516615731, Iran.
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27
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Werner JM, Wolf L, Tscherpel C, Bauer EK, Wollring M, Ceccon G, Deckert M, Brunn A, Pappesch R, Goldbrunner R, Fink GR, Galldiks N. Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas. J Neurooncol 2022; 159:309-317. [PMID: 35716310 PMCID: PMC9424167 DOI: 10.1007/s11060-022-04066-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/09/2022] [Indexed: 11/22/2022]
Abstract
Background The phase 2 REGOMA trial suggested an encouraging overall survival benefit in glioblastoma patients at first relapse treated with the multikinase inhibitor regorafenib. Here, we evaluated the efficacy and side effects of regorafenib in a real-life setting. Methods From 2018 to 2021, 30 patients with progressive WHO CNS grade 3 or 4 gliomas treated with regorafenib (160 mg/day; first 3 weeks of each 4-week cycle) with individual dose adjustment depending on toxicity were retrospectively identified. Side effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). MRI was obtained at baseline and after every second cycle. Tumor progression was assessed according to RANO criteria. After regorafenib initiation, the median PFS and OS were calculated. Results The median number of treatment lines before regorafenib was 2 (range 1–4). Most patients (73%) had two or more pretreatment lines. At first relapse, 27% of patients received regorafenib. A total of 94 regorafenib cycles were administered (median 2 cycles; range 1–9 cycles). Grade 3 and 4 side effects were observed in 47% and 7% of patients, respectively, and were not significantly increased in patients with two or more pretreatments (P > 0.05). The most frequent grade 3 or 4 side effects were laboratory abnormalities (62%). PFS was 2.6 months (range 0.8–8.2 months), and the OS was 6.2 months (range 0.9–24 months). Conclusions In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects.
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Affiliation(s)
- Jan-Michael Werner
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany
| | - Lena Wolf
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany
| | - Caroline Tscherpel
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany.,Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Leo-Brandt-St. 5, 52425, Juelich, Germany
| | - Elena K Bauer
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany
| | - Michael Wollring
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany.,Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Leo-Brandt-St. 5, 52425, Juelich, Germany
| | - Garry Ceccon
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany
| | - Martina Deckert
- Institute. of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center of Integrated Oncology (CIO), Universities of Aachen, Bonn, Cologne, and Düsseldorf, Cologne, Germany
| | - Anna Brunn
- Institute. of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Roberto Pappesch
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Roland Goldbrunner
- Center of Integrated Oncology (CIO), Universities of Aachen, Bonn, Cologne, and Düsseldorf, Cologne, Germany.,Deptartment of General Neurosurgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Gereon R Fink
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany.,Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Leo-Brandt-St. 5, 52425, Juelich, Germany
| | - Norbert Galldiks
- Deptartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener St. 62, 50937, Cologne, Germany. .,Institute of Neuroscience and Medicine (INM-3), Research Center Juelich, Leo-Brandt-St. 5, 52425, Juelich, Germany. .,Center of Integrated Oncology (CIO), Universities of Aachen, Bonn, Cologne, and Düsseldorf, Cologne, Germany.
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Hou JY, Xiao YT, Huang JB, Jiang XH, Jiang K, Li X, Xu L, Chen MS. Real-Life Experience of Regorafenib in Patients With Advanced Hepatocellular Carcinoma. Front Pharmacol 2022; 13:917384. [PMID: 35734398 PMCID: PMC9207200 DOI: 10.3389/fphar.2022.917384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The RESORCE trial reported that regorafenib was effective as the second-line treatment for patients with hepatocellular carcinoma (HCC) after progression on sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Objective: We aimed to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC. Patients and Methods: A total of 41 patients with advanced HCC who did not respond to sorafenib and followed a regorafenib regimen were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), radiological responses, and adverse events (AEs) were evaluated. Survival curves were compared by using the log-rank test and constructed with the Kaplan–Meier method. Results: The median PFS with regorafenib was 6.6 months (range: 5.0–8.2 months), and the median OS with regorafenib was not reached. The 1-year OS rate of regorafenib was 66.4%. The median OS of sequential sorafenib to regorafenib treatment was 35.3 months [95% confidence interval (CI), 24.3–46.3], and the 2-year OS rate of sequential sorafenib to regorafenib treatment was 74.4%. The most common AEs of regorafenib treatment were elevated aspartate aminotransferase [17/41 patients (41.5%)], elevated alanine aminotransferase [16/41 patients (39%)] and hand-foot syndrome [14/41 patients (34.1%)]. Conclusion: Regorafenib appears to be safe and clinically effective in patients with advanced HCC who progressed on first-line sorafenib.
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Affiliation(s)
- Jing-Yu Hou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Ya-ting Xiao
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
| | - Jing-Bo Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, China
| | - Xin-Hua Jiang
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Kai Jiang
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xun Li
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
| | - Min-Shan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
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29
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Yoshida Y, Sasaoka S, Tanaka M, Matsumoto K, Inoue M, Satake R, Shimada K, Mukai R, Suzuki T, Iwata M, Goto F, Mori T, Mori K, Yoshimura T, Nakamura M. Analysis of drug-induced hand-foot syndrome using a spontaneous reporting system database. Ther Adv Drug Saf 2022; 13:20420986221101963. [PMID: 35646307 PMCID: PMC9136434 DOI: 10.1177/20420986221101963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 04/23/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose The aim of our study was to assess the clinical features of hand-foot syndrome (HFS) associated with certain systemic chemotherapeutic drugs in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods HFS was defined using the preferred terms from the Medical Dictionary for Regulatory Activities. We used several indices, such as the reporting odds ratios (RORs) at 95% confidence interval (CI), the time-to-onset profile of HFS, and cluster analysis. Results Of 646,779 reports (submission period: April 2004 to September 2020), 1814 reported HFS events. The RORs (95% CI) for axitinib, capecitabine, lapatinib, regorafenib, sorafenib, and sunitinib were 14.9 (11.1-20.1), 54.6 (49.2-60.6), 130.4 (110.7-153.6), 63.3 (55.2-72.6), 29.0 (25.8-32.7), and 13.9 (11.7-16.5), respectively. The analysis of time-to-onset profiles revealed that the median values (interquartile range: 25.0-75.0%) of drug-induced HFS caused by capecitabine, cisplatin, docetaxel, everolimus, regorafenib, sorafenib, and trastuzumab were 21.0 (13.0-42.0), 15.0 (10.0-82.0), 6.0 (3.0-25.0), 86.5 (67.0-90.5), 9.0 (6.0-14.0), 9.0 (6.0-14.0), and 70.0 (15.0-189.0) days, respectively. The number of clusters was set to 4. Among these, one cluster, which included capecitabine, regorafenib, and lapatinib, exhibited a higher reporting ratio and ROR of drug-induced HFS than other drugs. Conclusions The RORs and results of time-to-onset analysis obtained in this study indicated the potential risk of HFS associated with chemotherapeutic drugs. Our results suggest that health care professionals must be aware of the potential onset of drug-induced HFS with docetaxel, regorafenib, and sorafenib for at least 4 weeks; therefore, careful observation is recommended. Plain Language Summary Elucidation of the relationship between cancer drugs and risk of hand-foot syndrome: Purpose: Hand-foot syndrome (HFS) is an adverse effect of some cancer drugs, which is characterized by symptoms such as redness, swelling, blistering, and pain in the area of palms and soles. HFS reduces the quality of life of patients and can sometimes interfere with anticancer treatment plans. It is important to understand the clinical manifestations of HFS and gain knowledge that will allow for early intervention by clinicians.Methods: In this study, we used a large-scale side effect database of real-world cases for a comprehensive investigation of anticancer-drug-induced HFS. The database contained 646,779 adverse event reports from April 2004 to September 2020; among which, we identified 1814 HFS events. Using these data, we could obtain information on the relationship between 19 types of anticancer drugs and HFS, and the onset time of HFS and HFS prognosis related to each anticancer drug. Results: Our results suggest that clinicians should monitor the risk of HFS with docetaxel, regorafenib, and sorafenib for at least the first 4 weeks after drug administration. Conclusion: These findings are crucial for improving the management of the adverse effects caused by anticancer drugs.
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Affiliation(s)
- Yu Yoshida
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Sayaka Sasaoka
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Mizuki Tanaka
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Kiyoka Matsumoto
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Misaki Inoue
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Riko Satake
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Kazuyo Shimada
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Ririka Mukai
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Takaaki Suzuki
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
- Gifu Prefectural Government, Gifu, Japan
| | - Mari Iwata
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
- Kifune Pharmacy, Gifu, Japan
| | - Fumiya Goto
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan
| | - Takayuki Mori
- Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Japan
| | - Koki Mori
- Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Japan
| | | | - Mitsuhiro Nakamura
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
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Li YM, Xu C, Sun B, Zhong FJ, Cao M, Yang LY. Piezo1 promoted hepatocellular carcinoma progression and EMT through activating TGF-β signaling by recruiting Rab5c. Cancer Cell Int 2022; 22:162. [PMID: 35461277 PMCID: PMC9035260 DOI: 10.1186/s12935-022-02574-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 04/06/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Piezo1 has been revealed to play a regulatory role in vascular development and progression of variety tumors. However, whether and how the progression of hepatocellular carcinoma (HCC) regulated by Piezo1 remains elusive. This study aimed to elucidate the effect and mechanisms of Piezo1 in HCC. METHODS The mRNA and protein expression level of Piezo1 in HCC samples and cell lines was determined by qRT-PCR, western blot and immunohistochemistry analyses. Two independent study cohorts containing 280 patients were analyzed to reveal the association between Piezo1 expression and clinicopathological characteristics. Series of in vitro and in vivo experiments were used to validate the function of Piezo1 in HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. Immunoprecipitation, immunofluorescence and in vitro and in vivo experiments were used to explore the molecular mechanism of Piezo1 in HCC progression. RESULTS Our results demonstrated the Piezo1 expression was significantly upregulated in HCC tissues and cell lines, and upregulation of Piezo1 closely correlated with aggressive clinicopathological features and poor prognosis. Knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly restrained proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, metastasis, EMT in vivo. TGF-β signaling pathway was most significant enriched pathway in GSEA. Finally, tumor promotion effect of Piezo1 was found to exerted through recruiting and combining Rab5c to activating TGF-β signaling pathway. CONCLUSIONS Piezo1 significantly related to poor prognosis and promotes progression of hepatocellular carcinoma via activating TGF-β signaling, which suggesting that Piezo1 may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.
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Affiliation(s)
- Yi-ming Li
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
| | - Cong Xu
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
| | - Bo Sun
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
| | - Fang-jing Zhong
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
| | - Momo Cao
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
| | - Lian-yue Yang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008 Hunan China
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31
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Akce M, El-Rayes BF, Bekaii-Saab TS. Frontline therapy for advanced hepatocellular carcinoma: an update. Therap Adv Gastroenterol 2022; 15:17562848221086126. [PMID: 35432597 PMCID: PMC9006370 DOI: 10.1177/17562848221086126] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/21/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer-related mortality in the United States and is projected to be the third leading cause of cancer-related mortality in the United States by 2030. Main risk factors include alcoholic cirrhosis, chronic hepatitis B, hepatitis C, and nonalcoholic steatohepatitis (NASH). More than half of the patients have advanced-stage disease at presentation. Currently approved frontline systemic therapy options include sorafenib, lenvatinib, and atezolizumab/bevacizumab. Over the past decade, there has been a significant improvement in survival with a median overall survival of 19.2 months reported with first-line treatment with atezolizumab/bevacizumab. Based on positive results of randomized phase III HIMALAYA trial, durvalumab and tremelimumab combination could become another frontline option. Multiple frontline clinical trials with immune checkpoint inhibitor (ICI) or ICI combined with other novel agents are underway. In the frontline setting, identifying predictive biomarkers for ICI-based or tyrosine kinase (TKI)-based therapy is an unmet need. Subsequent treatment is poorly defined in patients with prior ICI-based therapy since all the available second-line and beyond therapy was studied after first-line sorafenib. Frontline systemic therapy is poorly defined in certain subgroups of HCC such as Child-Pugh B and post-transplant recurrent HCC. The landscape of frontline HCC treatment is rapidly changing, and this article reviews the most recent treatment approaches to frontline therapy for advanced HCC.
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Affiliation(s)
- Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Bassel F. El-Rayes
- Division of Hematology and Oncology, Department of Internal Medicine, O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA
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Anwer KE, El-Sattar NEAA, Shamaa MM, Zakaria MY, Beshay BY. Design, Green Synthesis and Tailoring of Vitamin E TPGS Augmented Niosomal Nano-Carrier of Pyrazolopyrimidines as Potential Anti-Liver and Breast Cancer Agents with Accentuated Oral Bioavailability. Pharmaceuticals (Basel) 2022; 15:ph15030330. [PMID: 35337128 PMCID: PMC8949375 DOI: 10.3390/ph15030330] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 02/01/2023] Open
Abstract
VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the “DFG out” motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound’s oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).
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Affiliation(s)
- Kurls E. Anwer
- Heterocyclic Synthesis Laboratory, Department of Chemistry, Faculty of Science, Ain Shams University, Cairo 11566, Egypt;
| | - Nour E. A. Abd El-Sattar
- Heterocyclic Synthesis Laboratory, Department of Chemistry, Faculty of Science, Ain Shams University, Cairo 11566, Egypt;
- Correspondence: (N.E.A.A.E.-S.); or (M.Y.Z.); Tel.: +20-1012277219 (N.E.A.A.E.-S.); +20-1006886853 (M.Y.Z.)
| | - Marium M. Shamaa
- Clinical and Biological Sciences (Biochemistry and Molecular Biology) Department, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria P.O. Box 1029, Egypt;
| | - Mohamed Y. Zakaria
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt
- Correspondence: (N.E.A.A.E.-S.); or (M.Y.Z.); Tel.: +20-1012277219 (N.E.A.A.E.-S.); +20-1006886853 (M.Y.Z.)
| | - Botros Y. Beshay
- Pharmaceutical Sciences (Pharmaceutical Chemistry) Department, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria P.O. Box 1029, Egypt;
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Ronnebaum S, Aly A, Patel D, Benavente F, Rueda JD. Systematic literature review of trials assessing recommended systemic treatments in hepatocellular carcinoma. Hepat Oncol 2022; 9:HEP41. [PMID: 34765109 PMCID: PMC8577513 DOI: 10.2217/hep-2021-0003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 08/03/2021] [Indexed: 02/08/2023] Open
Abstract
AIM To identify and evaluate the similarity of all trials assessing recommended treatments for advanced hepatocellular carcinoma. MATERIALS & METHODS Single arm and randomized trials from any phase and published any time up to February 2021 were systematically searched. RESULTS From 5677 records reviewed, 50 trials were included in the review, and 24 for assessed for similarity. In the first-line (1L) setting, several trials assessing sorafenib were noted for enrolling patients with more severe disease and/or performance status than other 1L trials; trials within the second-line (2L) setting were generally similar. Median survival was <2 years in all trial arms. CONCLUSIONS Trials assessing recommended treatments are largely similar and appropriate for quantitative comparisons of several efficacy and safety outcomes.
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Altaf S, Saleem F, Sher AA, Ali A. Potential therapeutic strategies to combat HCC. Curr Mol Pharmacol 2022; 15:929-942. [PMID: 34979895 DOI: 10.2174/1874467215666220103111009] [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: 02/16/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a complex, life threatening and most common neoplasm in the world. HCC tumors are genetically and phenotypically heterogeneous and involve various molecular mechanisms and stimulation of several signaling pathways such as Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptors (EGFR), Insulin growth factor, Ras/extracellular signal-stimulated kinase, mammalian goal of rapamycin (mTOR), c-mesenchymal-epithelial transition factor-1 (c-Met), Hedgehog, Wnt and apoptotic signaling. Lately, in patient's multi-kinase cascade blockers such as sorafenib, selumetinib and regorafenib have increased survival rate of progressive HCC. This development presents a step forward towards the therapy of liver cancer infection and attests that molecular systemic rehabilitations can be useful in HCC treatment. The development of these systemic therapeutic agents has further expanded the research area for surplus molecular mediators to auxiliary increase cure rate of patients. This article reviews the complete consideration of focus on cascades, current enduring clinical tests by means of HCC therapeutic mediators, and imminent prospects in the cure of HCC.
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Affiliation(s)
- Sidra Altaf
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Faiza Saleem
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Azam Ali Sher
- Department of Epidemiology, Michigan State University, Michigan, USA
| | - Ashiq Ali
- Department of Pathology, University of Agriculture, Faisalabad, Pakistan
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35
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Kenda M, Avsec D, Zore T, Kogovšek E, Pečar Fonović U, Kos J, Bozovičar K, Bratkovič T, Karas Kuželički N, Žegura B, Filipič M, Sollner Dolenc M. Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors. Toxicol Appl Pharmacol 2022; 434:115818. [PMID: 34890638 DOI: 10.1016/j.taap.2021.115818] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/24/2021] [Accepted: 12/02/2021] [Indexed: 11/25/2022]
Abstract
Modern anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of androgen receptor, estrogen receptor α (ERα), glucocorticoid receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1-5 μM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.
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Affiliation(s)
- Maša Kenda
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Damjan Avsec
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Taja Zore
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Eva Kogovšek
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Urša Pečar Fonović
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Janko Kos
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Krištof Bozovičar
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | - Tomaž Bratkovič
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
| | | | - Bojana Žegura
- National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000 Ljubljana, Slovenia.
| | - Metka Filipič
- National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000 Ljubljana, Slovenia.
| | - Marija Sollner Dolenc
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
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An L, Liao H, Yuan K. Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: A Meta-analysis. J Clin Transl Hepatol 2021; 9:868-877. [PMID: 34966650 PMCID: PMC8666373 DOI: 10.14218/jcth.2021.00054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/05/2021] [Accepted: 04/26/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND AIMS In the last decade, several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC) have been reported. But the outcomes were different from each other. This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC. METHODS Embase (1974 to October 2019) and Ovid MEDLINE (1946 to October 2019) were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC. The quality of each study was assessed by the modified Jadad scale. Statistical analysis was carried out by RevMan5.3 software. Efficacy and safety were analyzed. Efficacy included overall survival (OS), disease control rate, time to progression, and progression-free survival. RESULTS Eight studies involving 3,173 patients were eligible. No difference in OS was found between the second-line treatment group and the control group (HR=0.87, 95% CI: 0.74-1.01, p=0.06). Disease control rate (relative risk (RR)=1.36, 95% CI: 1.16-1.60, p=0.0002), time to progression (HR=0.64, 95% CI: 0.51-0.81, p=0.0002) and progression-free survival (HR=0.60, 95% CI: 0.46-0.77, p<0.0001) were significantly improved by the second-line therapies. There was a slight difference in adverse events of any grade (RR=1.07, 95% CI: 1.00-1.14, p=0.03) between the two groups. CONCLUSIONS These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC. Compared with other second-line therapies, regorafenib seemed to be more effective.
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Affiliation(s)
- Limin An
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Haotian Liao
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
| | - Kefei Yuan
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, China
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Correspondence to: Kefei Yuan, Laboratory of Liver Surgery, West China Hospital, Sichuan University, 37 Guoxue lane, Wuhou District, Chengdu, Sichuan 610041, China. ORCID: https://orcid.org/0000-0003-4308-7743. Tel: +86-28-8542-2114, Fax: +86-28-8558-2944, E-mail:
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Deng Z, Huang K, Liu D, Luo N, Liu T, Han L, Du D, Lian D, Zhong Z, Peng J. Key Candidate Prognostic Biomarkers Correlated with Immune Infiltration in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:1607-1622. [PMID: 34956967 PMCID: PMC8694277 DOI: 10.2147/jhc.s337067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/18/2021] [Indexed: 12/29/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which causes ~800,000 deaths annually world-wide. Immune checkpoint inhibitor (ICI) has reformed cancer therapy and achieved unprecedented results in various malignancies, including HCC. However, the response rate of immunotherapy is very low in HCC. Considereing the complicated and unique immune status in liver, we hypothesize that critical molecules will affect prognosis and correlate with immune context in the tumor microenvironment of HCC. Methods Using Kaplan–Meier plotter, GEPIA2 and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), survival genes and their prognostic value were estimated in HCC. Based on Tumor Immune Estimation Resource (TIMER), association between survival genes and immune infiltration was examined in HCC. FunRich and STRING were used to analyze gene ontology and protein–protein interaction (PPI) Network, qRT-PCR was used to measure mRNA level of candidates; and a Cell Counting Kit-8 was used to measure proliferation of HCC cell line. Results Using multiple databases, we identified 36 key prognostic genes highly expressed in HCC and associated with poor survival of patients. Meanwhile, the 36 gene signatures correlated with immune infiltration in HCC. Moreover, these genes were significantly associated with exhausted T cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in HCC. Among the 36 key genes, SKA3, SGOL2, SPINDOC, TEDC2, TMCO3 and NUP205 were highly expressed in tumor samples compared with adjacent normal tissues in our HCC cohort (n=22). Additionally, proliferation of SMMC7721 cell line was inhibited when it interfered with SiRNA of each gene. Conclusion The 36 genes may serve as potential prognostic biomarkers and molecular targets to ameliorate tumor immune microenvironment (TIME) in HCC and therefore represent a novel avenue for individualized immunotherapy in HCC.
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Affiliation(s)
- Zenghua Deng
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Kanghua Huang
- Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Dongfang Liu
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Nan Luo
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Tingting Liu
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Long Han
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Dexiao Du
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China
| | - Dongbo Lian
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
| | - Zhaohui Zhong
- Department of General Surgery, Peking University People's Hospital, Beijing, 100044, People's Republic of China
| | - Jirun Peng
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China.,Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People's Republic of China
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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Nandi D, Cheema PS, Singal A, Bharti H, Nag A. Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1. Front Oncol 2021; 11:751271. [PMID: 34900697 PMCID: PMC8652299 DOI: 10.3389/fonc.2021.751271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 11/04/2021] [Indexed: 12/28/2022] Open
Abstract
The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.
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Affiliation(s)
| | | | - Aakriti Singal
- Department of Biochemistry, University of Delhi, New Delhi, India
| | - Hina Bharti
- Department of Biochemistry, University of Delhi, New Delhi, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi, New Delhi, India
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40
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Pathak S, Sonbol MB. Second-Line Treatment Options for Hepatocellular Carcinoma: Current Landscape and Future Direction. J Hepatocell Carcinoma 2021; 8:1147-1158. [PMID: 34584898 PMCID: PMC8464222 DOI: 10.2147/jhc.s268314] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is a leading cause of mortality worldwide, and its incidence is rising. The last few years have witnessed a proliferation of available systemic therapeutic options, with the approval of multiple agents, including immune checkpoint inhibitors and drugs targeting vascular endothelial growth factor, such as cabozantinib, regorafenib, and ramucirumab. Most recently, the combination of atezolizumab plus bevacizumab has resulted in the longest overall survival yet known in hepatocellular carcinoma, therefore changing the preferred first-line treatment from the previous options of sorafenib and lenvatinib. The aim of this review is to summarize the available clinical data for the current second-line systemic treatment options and the future perspectives in the treatment landscape of hepatocellular carcinoma.
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Affiliation(s)
- Surabhi Pathak
- Hematology-Oncology, King’s Daughters Medical Center, Ashland, KY, USA
| | - Mohamad Bassam Sonbol
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, USA
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Luo T, Zhang FX, Zhao K, Gao HY, Zhang SG, Wang L, Dou GF, Liu T, Yu M, Zhan YQ, Chen H, Yang XM, Li CY. Preclinical Pharmacokinetics, Tissue Distribution, and Primary Safety Evaluation of Indo5, a Novel Selective Inhibitor of c-Met and Trks. Front Pharmacol 2021; 12:711126. [PMID: 34447310 PMCID: PMC8383318 DOI: 10.3389/fphar.2021.711126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/30/2021] [Indexed: 11/17/2022] Open
Abstract
The compound [3-(1H-benzimidazol-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone], known as Indo5, is a novel selective inhibitor of c-Met and Trks, and it is a promising anticancer candidate against hepatocellular carcinoma (HCC). Assessing the pharmacokinetic properties, tissue distribution, and toxicity of Indo5 is critical for its medicinal evaluation. A series of sensitive and specific liquid chromatography-tandem mass spectrometry methods were developed and validated to determine the concentration of Indo5 in rat plasma and tissue homogenates. These methods were then applied to investigate the pharmacokinetics and tissue distribution of Indo5 in rats. After intravenous injection of Indo5, the maximum concentration (Cmax) and the time at which Cmax was reached (Tmax) were 1,565.3 ± 286.2 ng/ml and 1 min, respectively. After oral administration, Cmax and Tmax were 54.7 ± 10.4 ng/ml and 2.0 ± 0.48 h, respectively. We calculated the absolute oral bioavailability of Indo5 in rats to be 1.59%. Following intravenous injection, the concentrations of Indo5 in various tissues showed the following order: liver > kidney ≈ heart > lung ≈ large intestine ≈ small intestine ≈ stomach > spleen > brain ≈ testes; hence, Indo5 distributed highest in the liver and could not cross the blood–brain or blood–testes barriers. Continuous injection of Indo5 for 21 days did not lead to liver injury, considering unchanged ALT and AST levels, normal histological architecture of the liver, and normal number and frequencies of immune cells in the liver, indicating a very low toxicity of Indo5 in vivo. Collectively, our findings provide a comprehensive understanding of the biological actions of Indo5 in vivo and further support its development as an antitumor treatment for HCC patients.
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Affiliation(s)
- Teng Luo
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,Beijing Institute of Radiation Medicine, Beijing, China.,Institute of NBC Defence, Beijing, China
| | - Fei-Xiang Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Ke Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Hui-Ying Gao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | | | - Lin Wang
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Gui-Fang Dou
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Ting Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xiao-Ming Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Wang H, Li W. Recent update on comprehensive therapy for advanced hepatocellular carcinoma. World J Gastrointest Oncol 2021; 13:845-855. [PMID: 34457190 PMCID: PMC8371518 DOI: 10.4251/wjgo.v13.i8.845] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/12/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The treatment methods for HCC are diverse, mainly including surgical resection, ablation, and liver transplantation. The curative effect can be achieved only for early stage HCC, and it is easy to recur and metastasize after surgery, with a 5-year recurrence rate as high as 70%. Most patients with HCC are in the middle and advanced stage at the time of diagnosis and lose the chance of surgical resection. In recent years, with the in-depth study of the pathogenesis of HCC and the progress of medical science and technology, the systemic treatment of advanced HCC has made a breakthrough. At present, multidisciplinary comprehensive treatment including targeted therapy and immunotherapy has become an effective strategy and inevitable trend for the treatment of advanced HCC. Combined therapy has greatly improved the prognosis of HCC patients and opened up a new milestone in the treatment of this malignancy. In this article, we focus on the treatment progress of advanced HCC to further guide clinical practice.
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Affiliation(s)
- Hui Wang
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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Liu C, Zhu X, Jia Y, Chi F, Qin K, Pei J, Zhang C, Mu X, Zhang H, Dong X, Xu J, Yu B. Dasatinib inhibits proliferation of liver cancer cells, but activation of Akt/mTOR compromises dasatinib as a cancer drug. Acta Biochim Biophys Sin (Shanghai) 2021; 53:823-836. [PMID: 33961012 DOI: 10.1093/abbs/gmab061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Indexed: 12/15/2022] Open
Abstract
Dasatinib is a multi-target protein tyrosine kinase inhibitor. Due to its potent inhibition of Src, Abl, the platelet-derived growth factor receptor (PDGFR) family kinases, and other oncogenic kinases, it has been investigated as a targeted therapy for a broad spectrum of cancer types. However, its efficacy has not been significantly extended beyond leukemia. The mechanism of resistance to dasatinib in a wide array of cancers is not clear. In the present study, we investigated the effect of dasatinib on hepatocellular carcinoma cell growth and explored the underlying mechanisms. Our results showed that dasatinib potently inhibited the proliferation of SNU-449 cells, but not that of other cell lines, such as SK-Hep-1, even though it inhibited the phosphorylation of Src on both negative and positive regulation sites in all these cells. Dasatinib activated the phosphoinositide-dependent protein kinase1 (PDK1)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in SK-Hep-1 cells, but not in SNU-449 cells. Blocking the Akt/mTOR signaling pathway strongly promoted the efficacy of dasatinib in SK-Hep-1 cells. In SNU-449 cells, dasatinib promoted apoptosis and the cleavage of caspase-3 and caspase-7, induced cell cycle arrest in the G1 phase, and inhibited the expression of Cyclin-dependent kinase (CDK4)/6/CyclinD1 complex. These findings demonstrate that dasatinib exerts its anti-proliferative effect on hepatocellular cell proliferation by blocking the Src family kinases; however, it causes Akt activation, which compromises dasatinib as an anti-cancer drug.
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Affiliation(s)
- Chang Liu
- Department of Biochemistry and Molecular Biology, Changzhi Medical College, Changzhi 046000, China
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Xiaoxia Zhu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Yuqi Jia
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Fenqing Chi
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Keru Qin
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Jinhong Pei
- Department of Biochemistry and Molecular Biology, Changzhi Medical College, Changzhi 046000, China
| | - Chan Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Xiuli Mu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
| | - Hongwei Zhang
- Department of Hematology, Affiliated Tumor Hospital of Shanxi Medical University, Taiyuan 030013, China
| | - Xiushan Dong
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan 030032, China
| | - Jun Xu
- Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Baofeng Yu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China
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Moon H, Ro SW. MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:3026. [PMID: 34204242 PMCID: PMC8234271 DOI: 10.3390/cancers13123026] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.
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Affiliation(s)
| | - Simon Weonsang Ro
- Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si 17104, Gyeonggi-do, Korea;
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45
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Cheng K, Liu CF, Rao GW. Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors. Curr Med Chem 2021; 28:2540-2564. [PMID: 32407259 DOI: 10.2174/0929867327666200514082425] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/18/2020] [Accepted: 04/23/2020] [Indexed: 11/22/2022]
Abstract
Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.
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Affiliation(s)
- Kang Cheng
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Chen-Fu Liu
- School of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
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Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, Benevento F, Piscaglia F, Tovoli F. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2021; 14:17562848211016959. [PMID: 34104211 PMCID: PMC8165525 DOI: 10.1177/17562848211016959] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib's efficacy in HCC that led to regorafenib's approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib's potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Via Albertoni 15, Bologna, 40138, Italy
- Division of Internal Medicine IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Ielasi
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Vito Sansone
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italia
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Granito A, Marinelli S, Forgione A, Renzulli M, Benevento F, Piscaglia F, Tovoli F. Regorafenib Combined with Other Systemic Therapies: Exploring Promising Therapeutic Combinations in HCC. J Hepatocell Carcinoma 2021; 8:477-492. [PMID: 34079777 PMCID: PMC8165211 DOI: 10.2147/jhc.s251729] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.
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Affiliation(s)
- Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Antonella Forgione
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Renzulli
- Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Benevento
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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48
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Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future. Anticancer Drugs 2021; 32:593-601. [PMID: 33929995 DOI: 10.1097/cad.0000000000001071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.
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Dipasquale A, Marinello A, Santoro A. A Comparison of Lenvatinib versus Sorafenib in the First-Line Treatment of Unresectable Hepatocellular Carcinoma: Selection Criteria to Guide Physician's Choice in a New Therapeutic Scenario. J Hepatocell Carcinoma 2021; 8:241-251. [PMID: 33884259 PMCID: PMC8055282 DOI: 10.2147/jhc.s270532] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy across the world. Alongside improvement in local approaches for early stages, the prognosis of patients with advanced disease remains poor. The tyrosine kinase inhibitor sorafenib was the first drug approved for advanced HCC. During the past decade, this has been extensively explored in real-life settings, such as Eastern Cooperative Oncology Group performance status 2, Child-Pugh B liver function, chronic kidney disease, HIV infection, transplant recipients and the elderly. After 10 years, the multikinase inhibitor lenvatinib was approved in first-line setting. The Phase III REFLECT trial established the non-inferiority of lenvatinib compared with sorafenib in terms of overall survival, meanwhile exploratory analysis suggests a potential benefit over sorafenib for patients with HBV chronic infection and positive alpha-fetoprotein value. Experience with lenvatinib for patients not matching the REFLECT trial criteria remains promising but still retrospective. Indeed, the treatment sequence after lenvatinib still remains a crucial issue, considering that standard second-line options were tested only in patients who progressed to sorafenib. Overall, the choice between lenvatinib and sorafenib should take into account key selection criteria from randomized trials, evidence to date in special clinical situations, the physician's experience and patient's preference. Fast approval of atezolizumab plus bevacizumab as first-line treatment for advanced HCC brought an additional element in this scenario. Undoubtedly, lenvatinib and sorafenib remain available options for patients who are not suitable or those progressed to combination immunotherapy. It is conceivable that new systemic options will contribute to design a new treatment algorithm for HCC in the near future. Meanwhile, prospective studies and biomarker analysis are needed to help physicians in the choice between lenvatinib and sorafenib.
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Affiliation(s)
- Angelo Dipasquale
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Italy.,IRCCS Humanitas Research Hospital, Rozzano, 20089, Italy
| | - Arianna Marinello
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Italy.,IRCCS Humanitas Research Hospital, Rozzano, 20089, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Italy.,IRCCS Humanitas Research Hospital, Rozzano, 20089, Italy
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50
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Shao YY, Cheng AL, Hsu CH. An Underdiagnosed Hypothyroidism and Its Clinical Significance in Patients with Advanced Hepatocellular Carcinoma. Oncologist 2021; 26:422-426. [PMID: 33687750 DOI: 10.1002/onco.13755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 02/02/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Many systemic therapies for advanced hepatocellular carcinoma (HCC) may cause hypothyroidism; however, in these patients, hypothyroidism prevalence before therapy and its prognostic impact remain unclear. MATERIALS AND METHODS We previously established a prospective cohort of patients who received sorafenib as first-line therapy for advanced HCC. No patients had been clinically diagnosed with hypothyroidism before or during sorafenib treatment. We retrospectively determined the levels of thyrotropin and free thyroxine before initiation of systemic therapy. Hypothyroidism was defined as thyrotropin level higher than the upper limit of the normal range. Among patients with hypothyroidism, free thyroxine level less than the lower normal range was defined as overt hypothyroidism, and free thyroxine level within the normal range was defined as subclinical hypothyroidism. RESULTS In total, 79 patients were enrolled; of them, 16 (20%) had hypothyroidism (overt hypothyroidism, 10; subclinical hypothyroidism, 6). Patients with hypothyroidism, compared with those without hypothyroidism, were more likely to be older than 65 years (56% vs. 29%, p = .037), have a serum α-fetoprotein level of >400 ng/mL (81% vs. 52%, p = .037), and have a significantly poorer overall survival (OS; median, 5.5 vs. 11.6 months, p = .043). After adjusting for other potential prognostic factors, hypothyroidism remained an independent predictor for poorer OS (hazard ratio, 2.53, p = .018). Patients with overt hypothyroidism and subclinical hypothyroidism exhibited similarly poor OS (p = .768). CONCLUSION Underdiagnosis of hypothyroidism in patients with advanced HCC was common. Hypothyroidism, whether overt or subclinical, is associated with poor prognosis of advanced HCC. IMPLICATIONS FOR PRACTICE The results of this study showed the underdiagnosis of hypothyroidism in patients with advanced hepatocellular carcinoma (HCC) and its influence on prognosis. These findings implied the importance of thyroid function check before initiation of systemic therapy for patients with advanced HCC.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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