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1
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Gilbert TM, Randle L, Quinn M, McGreevy O, O'leary L, Young R, Diaz-Neito R, Jones RP, Greenhalf B, Goldring C, Fenwick S, Malik H, Palmer DH. Molecular biology of cholangiocarcinoma and its implications for targeted therapy in patient management. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:108352. [PMID: 38653586 DOI: 10.1016/j.ejso.2024.108352] [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: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.
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Affiliation(s)
- T M Gilbert
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK; Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK.
| | - L Randle
- Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK
| | - M Quinn
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK
| | - O McGreevy
- Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK
| | - L O'leary
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK
| | - R Young
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK; Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK
| | - R Diaz-Neito
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK
| | - R P Jones
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK; Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK
| | - B Greenhalf
- Liverpool Experimental Cancer Medicines Centre, University of Liverpool, Liverpool, UK
| | - C Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems Integrative and Molecular Biology, University of Liverpool, Liverpool, UK
| | - S Fenwick
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK
| | - H Malik
- Hepatobiliary Surgery, Liverpool University Hospitals NHS FT, Liverpool, UK
| | - D H Palmer
- Clatterbridge Cancer Centre, Liverpool, UK; Liverpool Experimental Cancer Medicines Centre, University of Liverpool, Liverpool, UK
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2
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Porreca V, Barbagallo C, Corbella E, Peres M, Stella M, Mignogna G, Maras B, Ragusa M, Mancone C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers (Basel) 2024; 16:2889. [PMID: 39199659 PMCID: PMC11352949 DOI: 10.3390/cancers16162889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/01/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices.
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Affiliation(s)
- Veronica Porreca
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Cristina Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Eleonora Corbella
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Marco Peres
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Michele Stella
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Giuseppina Mignogna
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Bruno Maras
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Marco Ragusa
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
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3
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Lozano E, Sanchon-Sanchez P, Morente-Carrasco A, Chinchilla-Tábora LM, Mauriz JL, Fernández-Palanca P, Marin JJG, Macias RIR. Impact of Aberrant β-Catenin Pathway on Cholangiocarcinoma Heterogeneity. Cells 2023; 12:cells12081141. [PMID: 37190050 DOI: 10.3390/cells12081141] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/β-catenin pathway plays a pivotal role. Alteration of β-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/β-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease.
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Affiliation(s)
- Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Sanchon-Sanchez
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Ana Morente-Carrasco
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Area of Physiology, Faculty of Health Sciences, University Rey Juan Carlos, 28032 Alcorcón, Madrid, Spain
| | | | - José L Mauriz
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Institute of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain
| | - Paula Fernández-Palanca
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Institute of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
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4
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Sae-fung A, Mutirangura A, Jitkaew S. Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma. Front Immunol 2023; 13:1051273. [PMID: 36733386 PMCID: PMC9887182 DOI: 10.3389/fimmu.2022.1051273] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous and aggressive malignancy of the bile ducts with a poor prognosis and high mortality rate. Effective targeted therapy and accurate prognostic biomarkers are still lacking. Ferroptosis is a form of regulated cell death implicated in cancer progression and has emerged as a potential therapeutic target in various cancers. However, a comprehensive analysis of ferroptosis-related genes (FRGs) for predicting CCA prognosis and therapeutic targets and determining the role of ferroptosis in CCA remain to be performed. Here, we developed a prognostic FRG signature using a least absolute shrinkage and selection operator Cox regression analysis in a training cohort. We then validated it using four independent public datasets. The six-FRG signature was developed to predict CCA patient survival, stratifying them into low-risk and high-risk groups based on survival time. Significantly, the high-risk CCA patients had shorter overall survival. A receiver operating characteristic curve analysis further confirmed the prognostic FRG signature's strong predictive ability, indicating that it was an independent prognostic indicator for CCA patients. Furthermore, the high-risk group was associated with fluke infection and high clinical stages. Cancer-associated fibroblast (CAF) score and CAF markers were significantly higher in the high-risk group than the low-risk group. Moreover, our FRG signature could predict immune checkpoint markers for immunotherapy and drug sensitivity. The mRNA expression levels of the six-FRG signature was validated in 10 CCA cell lines and dividing them into low-risk and high-risk groups using the FRG signature. We further showed that high-risk CCA cell lines were more resistant to ferroptosis inducers, including erastin and RSL3, than the low-risk CCA cell lines. Our study constructed a novel FRG signature model to predict CCA prognoses which might provide prognostic biomarkers and potential therapeutic targets for CCA patients. Ferroptosis sensitivity in high-risk and low-risk CCA cell lines suggests that ferroptosis resistance is associated with high-risk group CCA. Therefore, ferroptosis could be a promising therapeutic target for precision therapy in CCA patients.
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Affiliation(s)
- Apiwit Sae-fung
- Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Faculty of Medicine, Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Siriporn Jitkaew
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,*Correspondence: Siriporn Jitkaew,
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5
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Vatankhah F, Salimi N, Khalaji A, Baradaran B. Immune checkpoints and their promising prospect in cholangiocarcinoma treatment in combination with other therapeutic approaches. Int Immunopharmacol 2023; 114:109526. [PMID: 36481527 DOI: 10.1016/j.intimp.2022.109526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma (CCA) is one of the malignant tumors that has shown rapid development in incidence and mortality in recent years. Like other types of cancer, patients with CCA experience alterations in the expression of immune checkpoints, indicating the importance of immune checkpoint inhibitors in treating CCA. The results of TCGA analysis in this study revealed a marginal difference in the expression of important immune checkpoints, Programmed cell death 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and their ligands in CCA samples compared to normal ones. This issue showed the importance of combination therapy in this cancer. This review considers CCA treatment and covers several therapeutic modalities or combined treatment strategies. We also cover the most recent developments in the field and outline the important areas of immune checkpoint molecules as prognostic variables and therapeutic targets in CCA.
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Affiliation(s)
- Fatemeh Vatankhah
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Salimi
- School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Amirreza Khalaji
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, 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.
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6
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Sahashi H, Kato A, Yoshida M, Hayashi K, Naitoh I, Hori Y, Natsume M, Jinno N, Kachi K, Asano G, Toyohara T, Kito Y, Ammanamanchi S, Kataoka H. Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma. Front Oncol 2022; 12:963314. [PMID: 36212467 PMCID: PMC9539031 DOI: 10.3389/fonc.2022.963314] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/05/2022] [Indexed: 11/21/2022] Open
Abstract
Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA.
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Affiliation(s)
- Hidenori Sahashi
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Akihisa Kato
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
- *Correspondence: Akihisa Kato,
| | - Michihiro Yoshida
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Kazuki Hayashi
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yasuki Hori
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Makoto Natsume
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Naruomi Jinno
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Kenta Kachi
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Go Asano
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Tadashi Toyohara
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yusuke Kito
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Sudhakar Ammanamanchi
- Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ, United States
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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7
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Chulkova SV, Loginov VI, Podluzhnyi DV, Egorova AV, Syskova AY, Semichev DG, Gladilina IA, Kudashkin NE. [The role of molecular genetic factors in the development of cholangiocellular carcinoma]. Arkh Patol 2022; 84:76-83. [PMID: 35639847 DOI: 10.17116/patol20228403176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The article lists the main inducers of cholangiocarcinogenesis. The main inflammatory mediators (IL-6, nitric oxide, COX2) have been considered. Data on the study of gene mutations in cholangiocarcinomas are presented. The spectrum of genetic mutations depends on the biliary cancer origin (FGFR2 with intrahepatic cholangiocarcinoma, PRKACA, PRKACB with extrahepatic cholangiocarcinoma). Mutations in the KRAS, TP53, ARIAD1A genes are common in extrahepatic bile duct cancer. The role of epigenetic changes such as DNA hypermethylation, histone modifications, chromatin remodeling, as well as disturbances in miRNA expression is presented. A number of epigenetic features, such as the presence of a TP53 mutations with hypermethylation of p14ARF, DAPK, and/or ASC, correlate with a more aggressive course of the disease. The role of the SOX17 gene in the development of drug resistance is highlighted. The study of the molecular genetic features of extrahepatic bile duct cancer can help to better understand the pathogenesis of this type of tumor, to establish new prognostic and diagnostic markers of the disease.
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Affiliation(s)
- S V Chulkova
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - V I Loginov
- Scientific Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - D V Podluzhnyi
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
| | - A V Egorova
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - A Yu Syskova
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - D G Semichev
- N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - I A Gladilina
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
| | - N E Kudashkin
- N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.,N.I. Pirogov Russian National Research Medical University, Moscow, Russia
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Wu WS, Ling CH, Lee MC, Cheng CC, Chen RF, Lin CF, You RI, Chen YC. Targeting Src-Hic-5 Signal Cascade for Preventing Migration of Cholangiocarcinoma Cell HuCCT1. Biomedicines 2022; 10:biomedicines10051022. [PMID: 35625759 PMCID: PMC9138979 DOI: 10.3390/biomedicines10051022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/24/2022] [Accepted: 04/25/2022] [Indexed: 02/04/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer with poor prognosis. The deregulation of a lot of oncogenic signaling molecules, such as receptor tyrosine kinases (RTKs), has been found to be associated with CCA progression. However, RTKs-based target therapy showed limited improvement suggesting a need to search for alternative targets for preventing CCA progression. To address this issue, we screened the oncogenic signal molecules upregulated in surgical tissues of CCAs. Interestingly, over-expression of hydrogen peroxide inducible clone-5 (Hic-5) coupled with over-activation of Src, AKT, JNK were observed in 50% of the cholangiocarcinoma with metastatic potential. To investigate whether these molecules may work together to trigger metastatic signaling, their up-and-down relationship was examined in a well-established cholangiocarcinoma cell line, HuCCT1. Src inhibitors PP1 (IC50, 13.4 μM) and dasatinib (IC50, 0.1 μM) significantly decreased both phosphorylated AKT (phosphor-AKT Thr450) and Hic-5 in HuCCT1. In addition, a knockdown of Hic-5 effectively suppressed activation of Src, JNK, and AKT. These implicated a positive cross-talk occurred between Hic-5 and Src for triggering AKT activation. Further, depletion of Hic-5 and inhibition of Src suppressed HuccT1 cell migration in a dose-dependent manner. Remarkably, prior transfection of Hic-5 siRNA for 24 h followed by treatment with PP1 or dasatinib for 24 h resulted in additive suppression of HuCCT1 migration. This suggested that a promising combinatory efficacy can be achieved by depletion of Hic-5 coupled with inhibition of Src. In the future, target therapy against CCA progression by co-targeting Hic-5 and Src may be successfully developed in vivo.
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Affiliation(s)
- Wen-Sheng Wu
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
| | - Chin-Hsien Ling
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan;
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Chuan-Chu Cheng
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
| | - Rui-Fang Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
| | - Chen-Fang Lin
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
| | - Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan;
| | - Yen-Cheng Chen
- Division of General Surgery, Department of Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (W.-S.W.); (C.-H.L.); (C.-C.C.); (R.-F.C.); (C.-F.L.)
- School of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Correspondence:
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9
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Carotenuto M, Sacco A, Forgione L, Normanno N. Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:200-223. [PMID: 36046845 PMCID: PMC9400790 DOI: 10.37349/etat.2022.00079] [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: 12/18/2021] [Accepted: 02/22/2022] [Indexed: 11/22/2022] Open
Abstract
Improving the survival of patients with cholangiocarcinoma (CCA) has long proved challenging, although the treatment of this disease nowadays is on advancement. The historical invariability of survival outcomes and the limited number of agents known to be effective in the treatment of this disease has increased the number of studies designed to identify genetic targetable hits that can be efficacious for novel therapies. In this respect, the increasing feasibility of molecular profiling starting either from tumor tissue or circulating cell-free DNA (cfDNA) has led to an increased understanding of CCA biology. Intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) display different and typical patterns of actionable genomic alterations, which offer opportunity for therapeutic intervention. This review article will summarize the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease.
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Affiliation(s)
- Marianeve Carotenuto
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Alessandra Sacco
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Laura Forgione
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
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10
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Pavicevic S, Reichelt S, Uluk D, Lurje I, Engelmann C, Modest DP, Pelzer U, Krenzien F, Raschzok N, Benzing C, Sauer IM, Stintzing S, Tacke F, Schöning W, Schmelzle M, Pratschke J, Lurje G. Prognostic and Predictive Molecular Markers in Cholangiocarcinoma. Cancers (Basel) 2022; 14:1026. [PMID: 35205774 PMCID: PMC8870611 DOI: 10.3390/cancers14041026] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.
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Affiliation(s)
- Sandra Pavicevic
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sophie Reichelt
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Deniz Uluk
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Isabella Lurje
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Cornelius Engelmann
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Dominik P. Modest
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Uwe Pelzer
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (D.P.M.); (U.P.); (S.S.)
| | - Frank Tacke
- Department of Gastroenterology and Hepatology, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (C.E.); (F.T.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (S.P.); (S.R.); (D.U.); (F.K.); (N.R.); (C.B.); (I.M.S.); (W.S.); (M.S.); (J.P.)
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11
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RTK25: A Comprehensive Molecular Profiling Strategy in Cholangiocarcinoma Using an Integrated Bioinformatics Approach. Pharmaceuticals (Basel) 2021; 14:ph14090898. [PMID: 34577598 PMCID: PMC8469883 DOI: 10.3390/ph14090898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/28/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that primarily originate from the bile duct. Tumor heterogeneity is a prime characteristic of CCA and considering the scarcity of approved targeted therapy drugs, this makes precision oncology impractical in CCA. Stratifying patients based on their molecular signature and biomarker-guided therapy may offer a conducive solution. Receptors tyrosine kinases (RTK) are potential targets for novel therapeutic strategies in CCA as RTK signaling is dysregulated in CCA. This study aims to identify targetable RTK profile in CCA using a bioinformatic approach. We discovered that CCA samples could be grouped into molecular subtypes based on the gene expression profile of selected RTKs (RTK25). Using the RTK25 gene list, we discovered five distinct molecular subtypes of CCA in this cohort. Tyrosine kinase inhibitors that target each RTK profile and their subsequent molecular signatures were also discovered. These results suggest that certain RTKs correlate with each other, indicating that tailored dual inhibition of RTKs may be more favorable than monotherapy. The results from this study can direct future investigative attention towards validating this concept in in vivo and in vitro systems. Ultimately, this will facilitate biomarker-guided clinical trials for the successful approval of novel therapeutic options in CCA.
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12
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Di-Luoffo M, Pirenne S, Saandi T, Loriot A, Gérard C, Dauguet N, Manzano-Núñez F, Alves Souza Carvalhais N, Lamoline F, Cordi S, Konobrocka K, De Greef V, Komuta M, Halder G, Jacquemin P, Lemaigre FP. A Mouse Model of Cholangiocarcinoma Uncovers a Role for Tensin-4 in Tumor Progression. Hepatology 2021; 74:1445-1460. [PMID: 33768568 DOI: 10.1002/hep.31834] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 03/05/2021] [Accepted: 03/14/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis. APPROACH AND RESULTS To this end, we generated a mouse model which combines cholangiocyte-specific expression of KrasG12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. We found that mice expressing KrasG12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs), and, eventually, iCCAs. The histology of mouse and human IPNBs was similar, and mouse iCCAs displayed histological characteristics of human mucin-producing, large-duct-type iCCA. Signaling pathways activated in human iCCA were also activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We further provide evidence that tensin-4 (TNS4), which is stimulated by KRASG12D and SRY-related HMG box transcription factor 17, promotes tumor progression. CONCLUSIONS We developed a mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade which involves TNS4 and promotes tumor progression.
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Affiliation(s)
- Mickaël Di-Luoffo
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Sophie Pirenne
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium.,Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Thoueiba Saandi
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Axelle Loriot
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Claude Gérard
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Nicolas Dauguet
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium.,CYTF Platform, Université catholique de Louvain, Brussels, Belgium
| | | | | | - Florence Lamoline
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Sabine Cordi
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | | | - Vitaline De Greef
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Mina Komuta
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Georg Halder
- VIB Center for Cancer Biology and KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium
| | - Patrick Jacquemin
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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13
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Boilève A, Hilmi M, Delaye M, Tijeras-Raballand A, Neuzillet C. Biomarkers in Hepatobiliary Cancers: What is Useful in Clinical Practice? Cancers (Basel) 2021; 13:2708. [PMID: 34070929 PMCID: PMC8198554 DOI: 10.3390/cancers13112708] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice.
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Affiliation(s)
- Alice Boilève
- Gustave Roussy, Département de Médecine Oncologique, 94805 Villejuif, France;
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
| | - Marc Hilmi
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Matthieu Delaye
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
| | - Annemilaï Tijeras-Raballand
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- OncoMEGA, 75010 Paris, France
| | - Cindy Neuzillet
- GERCOR Group, 151 rue du Faubourg Saint-Antoine, 75011 Paris, France; (M.H.); (M.D.); (A.T.-R.)
- Département de Médecine Oncologique, Curie Institute, 92210 Saint-Cloud, France
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14
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Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance. Cancers (Basel) 2021; 13:cancers13102358. [PMID: 34068398 PMCID: PMC8153564 DOI: 10.3390/cancers13102358] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Cholangiocarcinoma, a tumor derived from epithelial cells of the biliary tree, is characterized by a dismal prognosis. Its late diagnosis, which makes surgical resection not an option for most patients, and its marked refractoriness to standard chemotherapy, justify its high position in the rank of the most lethal cancers. Identifying specific druggable genetic alterations constitutes a promising alternative for the use of personalized targeted anticancer agents, and immunotherapy, or drugs able to interact with proteins involved in the crosstalk between cancer and immune cells, could also be an option in the future. However, it has also been observed that some patients fail to respond to these new therapies or after an initial response, the disease progresses. Therefore, understanding the mechanisms of pharmacoresistance is of utmost importance to design more effective treatments. Abstract Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.
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15
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Rational Molecular Profiling of Receptor-Associated Late Transducer Peptide Selectivity Across Her/Rtk Kinases. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-021-10223-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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16
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Boilève A, Hilmi M, Smolenschi C, Ducreux M, Hollebecque A, Malka D. Immunotherapy in Advanced Biliary Tract Cancers. Cancers (Basel) 2021; 13:1569. [PMID: 33805461 PMCID: PMC8036747 DOI: 10.3390/cancers13071569] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/20/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.
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Affiliation(s)
- Alice Boilève
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
| | - Marc Hilmi
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - Cristina Smolenschi
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - Michel Ducreux
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
| | - Antoine Hollebecque
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Département D’Innovations Thérapeutiques et D’Essais Précoces, Gustave Roussy, F-94805 Villejuif, France;
| | - David Malka
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France; (A.B.); (C.S.); (M.D.); (A.H.)
- Université Paris-Saclay, F-91190 Saint-Aubin, France
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17
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Boilève A, Verlingue L, Hollebecque A, Boige V, Ducreux M, Malka D. Rare cancer, rare alteration: the case of NTRK fusions in biliary tract cancers. Expert Opin Investig Drugs 2021; 30:401-409. [PMID: 33641556 DOI: 10.1080/13543784.2021.1896703] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: For patients with advanced/unresectable biliary tract cancers, cisplatin-gemcitabine combination is the standard first-line treatment. Beyond the first line, the therapeutic arsenal is limited with minimal benefit. Biliary tract cancers exhibit one of the highest frequencies of targetable molecular alterations across cancer types, and several targeted therapies are emerging as treatment options.Areas covered:We discuss neurotrophic tyrosine kinase receptor gene (NTRK) fusions in biliary tract cancers and the use of NTRK inhibitors (now approved in a 'cancer-agnostic' way), mechanisms of resistance, and emerging second-generation NTRK inhibitors.Expert opinion: Despite their rarity in biliary tract cancers, NTRK fusions are promising molecular targets because i) NTRK inhibitors have proven highly effective in NTRK-rearranged cancers and are now approved in a 'cancer-agnostic' way; ii) emerging second-generation NTRK inhibitors may overcome secondary resistance; iii) NTRK rearrangements will be readily detectable with the generalization of next-generation-sequencing in biliary tract cancers, including the detection of other frequent gene rearrangements, such as those involving the fibroblast growth factor receptor 2 gene (FGFR2). However, more data are necessary regarding the prevalence and characteristics of NTRK fusions in biliary tract cancers and the efficacy of NTRK inhibitors in these patients.
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Affiliation(s)
- Alice Boilève
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - Loïc Verlingue
- Université Paris-Saclay, France.,Département D'innovations Thérapeutiques Et D'essais Précoces, Gustave Roussy, Villejuif, France
| | - Antoine Hollebecque
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France.,Département D'innovations Thérapeutiques Et D'essais Précoces, Gustave Roussy, Villejuif, France
| | - Valérie Boige
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - Michel Ducreux
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
| | - David Malka
- Département De Médecine Oncologique, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, France
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18
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Sutherland M, Ahmed O, Zaidi A, Ahmed S. Current progress in systemic therapy for biliary tract cancers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:1094-1107. [PMID: 33735541 DOI: 10.1002/jhbp.939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Biliary tract cancers (BTCs) are heterogeneous cancers that include cancers of the bile duct and gallbladder. Although they are relatively uncommon, most patients with BTC are diagnosed at advanced-stage disease with high mortality rates. Recently, systemic therapy options for patients with BTC have evolved. This paper reviews recent advancements in systemic therapy and the results of key clinical trials in BTC. METHODS A literature search in PubMed and Google Scholar was performed using keywords related to BTC and systemic therapy. Studies that were presented in major international cancer research conferences were also included. RESULTS The evidence shows that adjuvant capecitabine has been associated with a lower relapse rate in early-stage BTC. In unselected patients with advanced BTC, combination chemotherapy is a standard treatment option. However, with a better understanding of the molecular profile of BTC, there has been a shift toward targeted agents in BTC that have shown promising responses. The evolving data also support the evolving role of immunotherapy in patients with deficient DNA mismatch repair or PD-L1-positive BTC. DISCUSSION Systemic treatment options for BTC have improved. The future identification of new targets, novel compounds, and predictive markers is a key step toward the use of personalized medicine in BTC.
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Affiliation(s)
| | - Osama Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Adnan Zaidi
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
| | - Shahid Ahmed
- Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada
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19
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Rahnemai-Azar AA, Pawlik TM. Cholangiocarcinoma: shedding light on the most promising drugs in clinical development. Expert Opin Investig Drugs 2021; 30:419-427. [PMID: 33645382 DOI: 10.1080/13543784.2021.1897103] [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] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, The James Comprehensive Cancer Center, Columbus, OH, USA
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20
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Yang W, Sun Y. Promising Molecular Targets for the Targeted Therapy of Biliary Tract Cancers: An Overview. Onco Targets Ther 2021; 14:1341-1366. [PMID: 33658799 PMCID: PMC7920611 DOI: 10.2147/ott.s297643] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancer (BTC) is a leading cause of cancer-related death, due to the limited benefits of current systematic therapies and the heterogeneity of the tumor itself. High heterogeneity means that the clinical and molecular features vary between different subtypes of BTC, while the underlying molecular mechanisms remain unclear. Targeted therapy, where inhibitors are developed to selectively combine with targeted molecules in order to block abnormal signaling pathways in BTC, has shown promise as an emerging form of treatment for various types of cancer. In this article, a comprehensive review is conducted to examine potential molecular targets for BTC targeted therapy and their mechanisms. Furthermore, preliminary data published from clinical trials is utilized to analyze the main drugs used to combat BTC. The collective information presented in this article has provided useful insights into the current understanding of BTC.
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Affiliation(s)
- Wenwei Yang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yongkun Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
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21
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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22
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Chen J, Guan L, Fan P, Liu X, Liu R, Liu Y, Bai H. In vitro study of the effects of DC electric fields on cell activities and gene expression in human choriocarcinoma cells. Electromagn Biol Med 2021; 40:49-64. [PMID: 33179558 DOI: 10.1080/15368378.2020.1846555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/01/2020] [Indexed: 02/08/2023]
Abstract
Physiological electric fields (EFs), as one of the environmental cues influencing both normal and tumor cells, have profound effects on tumor cell malignancy potential. The cellular responses to EFs by choriocarcinoma cells and their underlying mechanisms are unknown. In this study, the migration/motility, cell cycle progression and proliferation of choriocarcinoma cells in electric field culture showed that choriocarcinoma cells migrated cathodally in an applied EF, and EF stimulation influenced cell cycle progression through G2/M arrest and therefore induced a reduction in cellular proliferation. The transcriptome of choriocarcinoma cells subjected to EF stimulation (150 mV/mm) was analyzed using RNA sequencing (RNA-Seq), and the results were verified by reverse transcription quantitative polymerase chain reaction. A Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that ErbB and HIF-1 signaling pathways that are involved in cell migration/motility, cell cycle progression and proliferation were significantly altered in cells treated with an EF of 150 mV/mm compared with control cells, and in addition, the downstream pathways of these signaling pathways such as AKT and P42/P44 MAPK (ERK1/2) showed primary activation by Western blotting. This study's results suggest that an applied EF is an effective cue in regulating cellular phenotypes of choriocarcinoma cells and that transcriptional analysis contributes to the understanding of the mechanism of EF-guided cell functions.
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Affiliation(s)
- Jinxin Chen
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University , Chengdu, P. R. China
- Department of Biochemistry, North Sichuan Medical College , Nanchong, P. R. China
| | - Linbo Guan
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University , Chengdu, P. R. China
| | - Ping Fan
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University , Chengdu, P. R. China
| | - Xinghui Liu
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University , Chengdu, P. R. China
| | - Rui Liu
- Division of Peptides Related with Human Disease, West China Hospital, Sichuan University , Chengdu, P. R. China
| | - Yu Liu
- Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University , Chengdu, P. R. China
| | - Huai Bai
- Laboratory of Genetic Disease and Perinatal Medicine and Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second University Hospital, Sichuan University , Chengdu, P. R. China
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23
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Lengyel CG, Habeeb B, Khan SZ, El Bairi K, Altuna SC, Hussain S, Mazher SA, Trapani D, Petrillo A. Role of Her-2 in Gastrointestinal Tumours beyond Gastric Cancer: A Tool for Precision Medicine. GASTROINTESTINAL DISORDERS 2020; 3:1-22. [DOI: 10.3390/gidisord3010001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) tumors account for a quarter of all the cancer burden and a third of the global cancer-related mortality. Among them, some cancers retain a dismal prognosis; therefore, newer and innovative therapies are urgently needed in priority disease areas of high-unmet medical need. In this context, HER2 could be a relevant prognostic and predictive biomarker acting as a target for specific drugs. However, if the role of HER2 has been object of investigation for several years in gastric cancer, it is not well established in other GI malignancies. The aim of this narrative review was to portray the current landscape of the potential role of HER2 as a predictive biomarker for GI tumors beyond gastric cancer. In colon cancer, the benefit from anti-HER2 therapies is less clear than in gastric neoplasms for the lack of controlled studies. Pancreatic, biliary tract adenocarcinomas and hepatocarcinoma may derive a less clear clinical benefit by using anti-HER2 agents in HER2 positive tumors. Overall, the results are promising and seem to suggest that the integration of multiple modalities of therapies can optimize the cancer care. However, further prospective trials are needed to validate the use of personalized targeted therapies in this field.
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Affiliation(s)
- Csongor G. Lengyel
- Head and Neck Surgery, National Institute of Oncology, 1122 Budapest, Hungary
| | - Baker Habeeb
- Medical Oncology Department, Shaqlawa Teaching Hospital, Erbil 44001, Iraq
| | - Shah Z. Khan
- Department of Clinical Oncology, BINOR Cancer Hospital, Bannu 28100, Pakistan
| | | | | | - Sadaqat Hussain
- Northwest Cancer Center, Western Health and Social Care Trust, Altnagelvin Hospital, Londonderry BT47 6SB, UK
| | - Syed Ayub Mazher
- UT Southwestern Clements University Hospital, Dallas, TX 75390, USA
| | - Dario Trapani
- European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, 80147 Naples, Italy
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Study of Campania “L.Vanvitelli”, 81100 Caserta, Italy
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24
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Jacobi O, Ross JS, Goshen-Lago T, Haddad R, Moore A, Sulkes A, Brenner B, Ben-Aharon I. ERBB2 Pathway in Biliary Tract Carcinoma: Clinical Implications of a Targetable Pathway. Oncol Res Treat 2020; 44:20-27. [PMID: 33279901 DOI: 10.1159/000511919] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/25/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS Current chemotherapy regimens for cholangiocarcinoma (CCA) yield poor outcomes, with a median overall survival of <12 months. Recent data on the genomic landscape of CCAs have created opportunities for targeted therapy. Yet, data regarding its efficacy are scarce. We aimed to describe the genomic landscape of a CCA patient cohort using next-generation sequencing (NGS), focusing on the ERBB/EFGR pathway and assessing response to anti-HER2 agents. METHODS Tissue samples of intrahepatic CCA (IHCC) and extrahepatic CCA (EHCC) underwent NGS for somatic aberrations. The clinical outcomes for patients treated with anti-HER2 agents were evaluated. RESULTS A total of 1,863 CCA cases (1,615 IHCCs and 248 EHCCs) underwent NGS, and they revealed a high prevalence of ERBB alterations (IHCC, 4.2%; EHCC, 9.7%). Among these, 23.8% of the IHCCs and 53.6% of the EHCCs had a point mutation in ERBB2, and 66.6% of the IHCCs and 41.2% of the EHCCs had ERBB copy number amplification. Three EHCC patients were diagnosed at our institute with ERBB/EGFR aberrations; 2 patients were treated with neratinib and 1 patient with a chemotherapy-trastuzumab combination. All 3 achieved disease stabilization and a clinical benefit. One patient underwent a liquid biopsy before and after 3 months of treatment, demonstrating disappearance of the ERBB2 clone and emergence of a Myc-mutated clone after treatment. CONCLUSIONS The genomic landscape of CCAs may harbor targetable alterations, especially in the ERBB/EGFR pathway. These alterations may have clinical significance in everyday practice.
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Affiliation(s)
- Oded Jacobi
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel,
| | | | - Tal Goshen-Lago
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel
| | - Riad Haddad
- Department of Surgery, Carmel Medical Center, Haifa, Israel
| | - Assaf Moore
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
| | - Aaron Sulkes
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
| | - Baruch Brenner
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
| | - Irit Ben-Aharon
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
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25
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Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: Current knowledge and future potential. J Cell Mol Med 2020; 25:618-628. [PMID: 33277810 PMCID: PMC7812297 DOI: 10.1111/jcmm.16151] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5‐year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early‐stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
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Affiliation(s)
- Mingxun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Pengyi Guo
- Department of Cardiothoracic Surgery, Ningbo Yinzhou NO.2 Hospital, Ningbo, China
| | - Yi Wang
- Department of Epidemiology and Biostatistics, Public Health and Management School, Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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26
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1459] [Impact Index Per Article: 291.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Ntanasis-Stathopoulos I, Tsilimigras DI, Gavriatopoulou M, Schizas D, Pawlik TM. Cholangiocarcinoma: investigations into pathway-targeted therapies. Expert Rev Anticancer Ther 2020; 20:765-773. [PMID: 32757962 DOI: 10.1080/14737140.2020.1807333] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma is a malignant disease of the biliary tract and accounts for 3% of all gastrointestinal tumors. Surgical intervention is currently the only potentially curative strategy for cholangiocarcinoma. For patients with unresectable, advanced or metastatic disease, the combination of gemcitabine with cisplatin is considered the standard treatment. However, currently available therapeutic options have only a marginal benefit, especially among patients with relapsed/refractory tumors. AREAS COVERED We reviewed targeted agents under clinical evaluation for patients with cholangiocarcinoma. FGFR and IDH inhibitors are at the most advanced stage of clinical investigation. EGFR inhibitors have demonstrated contradictory results, whereas inhibition of other molecular pathways, including the RAS/RAF/MEK/ERK, the MET, the PI3K/AKT/mTOR and angiogenetic pathways, has shown minimal or null benefit. EXPERT OPINION Several targeted approaches are being investigated for advanced cholangiocarcinoma. However, randomized clinical trials are needed to define the optimal treatment regimen and address issues including the option of monotherapy or combination regimens, the optimal sequence of different treatments, ways to overcome resistance to targeted treatments, as well as determining the right time and tissue for assessing molecular signatures. Targeted therapies and immunotherapy hold promise for improving patient outcomes in the future.
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Affiliation(s)
- Ioannis Ntanasis-Stathopoulos
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Cente , Columbus, OH, UAS
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
| | - Dimitrios Schizas
- Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens , Athens, Greece
| | - Timothy M Pawlik
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital , Athens, Greece
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28
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Emerging pathways for precision medicine in management of cholangiocarcinoma. Surg Oncol 2020; 35:47-55. [PMID: 32827952 DOI: 10.1016/j.suronc.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/06/2020] [Indexed: 12/27/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.
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29
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Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2319-2334. [PMID: 32606601 PMCID: PMC7296552 DOI: 10.2147/dddt.s250061] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 05/20/2020] [Indexed: 12/23/2022]
Abstract
Background Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models. Materials and Methods HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model. Results Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response. Conclusion Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.
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Affiliation(s)
- Hasaya Dokduang
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Wassana Jamnongkarn
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Bundit Promraksa
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Manida Suksawat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sureerat Padthaisong
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Malinee Thanee
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Jutarop Phetcharaburanin
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Nisana Namwat
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sakkarn Sangkhamanon
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Narong Khuntikeo
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Poramate Klanrit
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Watcharin Loilome
- Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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30
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Abstract
Cholangiocellular carcinoma (CCA) is one of the primary liver tumors and overall represents a rare malignancy; however, in recent years the incidence, particularly of intrahepatic CCA (iCCA) has increased worldwide. Due to the high mortality, CCAs cause a significant proportion of cancer-related deaths also in Germany. Because the diagnosis is often made in advanced stages of the disease, in many cases a surgical approach with curative intention is not possible. For locally advanced or metastatic CCA the combination of gemcitabine and cisplatin currently remains the only approved systemic treatment. As the average survival time is only approximately 12 months even under first-line treatment with gemcitabine/cisplatin, research is focused on developing new molecularly targeted and immunological treatment options. Various studies are currently being carried out to investigate approval options for targeted treatment, which could be considered for genetically altered tumors, e.g. in fibroblast growth factor receptor (FGFR) fusion and isocitrate dehydrogenase (IDH) mutations. Additionally, initial clinical data on immune checkpoint inhibitors are available for CCA. Due to the complex selection and partially limited applicability of current treatment options in patients with CCA, an early collaboration with a gastroenterology and oncology center with the possibility of supervision by a tumor board consisting of gastroenterological oncologists, surgeons, radiologists and radio-oncologists or in advanced stages by a molecular tumor board is essential.
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31
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Ejaz A, Cloyd JM, Pawlik TM. Advances in the Diagnosis and Treatment of Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2019; 27:552-560. [PMID: 31555936 DOI: 10.1245/s10434-019-07873-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) that arises from the biliary tract epithelium distal to the secondary biliary radicals. Over the past decade, significant advances have been made in the diagnosis, staging, and treatment of ICC. Emerging data have highlighted the importance of lymphadenectomy for elucidating patient prognosis as well as the at-risk nodal basins based on tumor location (de Jong et al. in J Clin Oncol 29(23):3140-3145, 2011). Several large randomized controlled trials have recently been published clarifying the role of adjuvant therapy for BTCs (Cloyd and Pawlik in J Oncol Pract 14(12):723-724, 2018). In addition, the molecular understanding of ICC pathogenesis has increased over time, leading to new potential molecular biomarkers and opening opportunities for novel targeted and immunologic therapies (Rizvi et al. in Nat Rev Clin Oncol 15(2):95-111, 2018). These recent advances serve to only improve our understanding of the optimal multidisciplinary treatment of this difficult disease.
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Affiliation(s)
- Aslam Ejaz
- James Cancer Center, The Ohio State University, Columbus, OH, USA. .,Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Jordan M Cloyd
- James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Timothy M Pawlik
- James Cancer Center, The Ohio State University, Columbus, OH, USA
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32
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Gurmikov BN, Kovalenko YA, Vishnevsky VA, Chzhao AV. Molecular genetic aspects of intrahepatic cholangiocarcinoma: literature review. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2019-6-1-37-43] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- B. N. Gurmikov
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - Yu. A. Kovalenko
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - V. A. Vishnevsky
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
| | - A. V. Chzhao
- A.V. Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia
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33
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Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer 2019; 19:185. [PMID: 30819129 PMCID: PMC6394015 DOI: 10.1186/s12885-019-5391-0] [Citation(s) in RCA: 200] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 02/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. CONCLUSION Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.
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Affiliation(s)
- Peter L. Labib
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - George Goodchild
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
| | - Stephen P. Pereira
- UCL Institute for Liver and Digestive Health, University College London (Royal Free Hospital Campus), Royal Free Hospital, Pond Street, London, NW3 2QG UK
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34
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Liu R, Kong Y, Sun P, Li F, Shi X. Correlation between methylation of the caveolin‐1 gene and of caveolin‐1 messenger ribonucleic acid, and protein levels and human epidermal growth factor receptor 2 protein expression in adenocarcinomas of the esophagogastric junction. PRECISION RADIATION ONCOLOGY 2019. [DOI: 10.1002/pro6.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Ruizhen Liu
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Yi Kong
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Pengbo Sun
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Faliang Li
- The First People's Hospital of Wu'an Wu'an Hebei China
| | - Xiaopeng Shi
- The First People's Hospital of Wu'an Wu'an Hebei China
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35
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Simile MM, Bagella P, Vidili G, Spanu A, Manetti R, Seddaiu MA, Babudieri S, Madeddu G, Serra PA, Altana M, Paliogiannis P. Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials. ACTA ACUST UNITED AC 2019; 55:medicina55020042. [PMID: 30743998 PMCID: PMC6409688 DOI: 10.3390/medicina55020042] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/13/2022]
Abstract
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.
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Affiliation(s)
- Maria Maddalena Simile
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy.
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36
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Lamarca A, Galdy S, Barriuso J, Moghadam S, Beckett E, Rogan J, Backen A, Billington C, McNamara MG, Hubner RA, Cramer A, Valle JW. The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers. PLoS One 2018; 13:e0206007. [PMID: 30335866 PMCID: PMC6193702 DOI: 10.1371/journal.pone.0206007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/04/2018] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Expression of human epidermal growth factor receptor (HER)2 and HER3 have been investigated in small BTC studies using variable scoring systems. METHODS HER2 and HER3 overexpression/amplification were explored following internationally agreed guidelines using immunohistochemistry (IHC) and fluorescent in-situ hybridisation (FISH), respectively. Logistic regression and survival analysis (Kaplan Meier, Log rank test and Cox Regression) were used for statistical analysis. RESULTS Sixty-seven eligible patients with Stage I/II (31.3%) or III/IV (68.7%) disease at diagnosis were included. Membrane HER2 overexpression/amplification was identified in 1 patient (1%). HER3 overexpression was predominantly cytoplasmic; the rate of overexpression/amplification of HER3 in membrane and cytoplasm was 16% [ampullary cancer (AMP) (1/13; 8%), gallbladder cancer (GBC) (1/10; 10%), intra-hepatic cholangiocarcinoma (ICC) (6/26; 23%), extra-hepatic cholangiocarcinoma (ECC) (3/18; 17%)] and 24% [AMP (1/13; 8%), GBC (1/10; 10%), ICC (10/26; 38%), ECC (4/18; 22%)], respectively. CONCLUSIONS A significant subset of patients with BTC expressed HER3. Inhibition of HER3 warrants further investigation. A better understanding of the downstream effects of HER3 in BTC requires further mechanistic investigations to identify new biomarkers and improve patient selection for future clinical trials.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Salvatore Galdy
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology, Milan, Italy
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Sharzad Moghadam
- Manchester Cancer Research Centre Biobank, University of Manchester, Manchester, United Kingdom
| | - Elizabeth Beckett
- The Christie Pathology Partnership, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Jane Rogan
- Manchester Cancer Research Centre Biobank, University of Manchester, Manchester, United Kingdom
| | - Alison Backen
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Catherine Billington
- The Christie Pathology Partnership, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Angela Cramer
- The Christie Pathology Partnership, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
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37
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ACGH detects distinct genomic alterations of primary intrahepatic cholangiocarcinomas and matched lymph node metastases and identifies a poor prognosis subclass. Sci Rep 2018; 8:10637. [PMID: 30006612 PMCID: PMC6045619 DOI: 10.1038/s41598-018-28941-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/03/2018] [Indexed: 12/17/2022] Open
Abstract
Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival.
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38
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Mertens JC, Ilyas SI, Gores GJ. Targeting cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1454-1460. [PMID: 28844952 PMCID: PMC6013079 DOI: 10.1016/j.bbadis.2017.08.027] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/16/2017] [Accepted: 08/21/2017] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA. Clinical trials targeting these specific driver mutations are in progress. However, The Tumor Genome Atlas (TCGA) marker analysis of CCA also highlights the tremendous molecular heterogeneity of this cancer rendering comprehensive employment of targeted therapies challenging. CCA also display a rich tumor microenvironment which may be easier to target. For example, targeting cancer associated fibroblasts for apoptosis with BH3-mimetics and/or and reversing T-cell exhaustion with immune check point inhibitors may help aid in the treatment of this otherwise devastating malignancy. Combinatorial therapy attacking the tumor microenvironment plus targeted therapy may help advance treatment for CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland.
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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39
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Lombardi P, Marino D, Fenocchio E, Chilà G, Aglietta M, Leone F. Emerging molecular target antagonists for the treatment of biliary tract cancer. Expert Opin Emerg Drugs 2018; 23:63-75. [PMID: 29468924 DOI: 10.1080/14728214.2018.1444749] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Biliary tract cancers (BTCs) are a heterogeneous group of cancers, characterized by low incidence but poor prognosis. Even after complete surgical resection for early stage, relapse is frequent and the lack of effective treatments contributes to the dismal prognosis. To date, the only standard treatment in first-line is cisplatin/gemcitabine combination, whereas no standard in 2nd-line has been defined. Hence, the current goal is to better understand the biology of BTCs, discovering new treatment methods and improving clinical outcomes. Areas covered: The development of next-generation-sequencing has unveiled the picture of the molecular signatures characterizing BTCs, leading to the identification of actionable mutations in biomarker-driven clinical trials. In this review we will cover the genetic landscape of BTC, focusing on the efficacy of existing treatments. Furthermore, we will discuss emerging molecular targets and evaluate the findings of pre-clinical studies. Finally, the encouraging results of clinical trials involving targeted therapies or immunotherapy will be reviewed. Expert opinion: FGFR fusion rearrangements and IDH1 or IDH2 mutations are the most promising targeted treatments under evaluation. In addition, innovative trial design will allow to offer a chance for tailored medicine to infrequent subgroups of BTCs patients based on their molecular features rather than their histology.
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Affiliation(s)
- Pasquale Lombardi
- a Department of Oncology , University of Turin Medical School , Turin , Italy
| | - Donatella Marino
- b Medical Oncology , Candiolo Cancer Institute - FPO- IRCCS , Candiolo , Italy
| | | | - Giovanna Chilà
- a Department of Oncology , University of Turin Medical School , Turin , Italy
| | - Massimo Aglietta
- a Department of Oncology , University of Turin Medical School , Turin , Italy.,b Medical Oncology , Candiolo Cancer Institute - FPO- IRCCS , Candiolo , Italy
| | - Francesco Leone
- a Department of Oncology , University of Turin Medical School , Turin , Italy
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40
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Xie J, Lu D, Li J, Wang J, Zhang Y, Li Y, Nie Q. Kernel differential subgraph reveals dynamic changes in biomolecular networks. J Bioinform Comput Biol 2017; 16:1750027. [PMID: 29281952 DOI: 10.1142/s0219720017500275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Many major diseases, including various types of cancer, are increasingly threatening human health. However, the mechanisms of the dynamic processes underlying these diseases remain ambiguous. From the holistic perspective of systems science, complex biological networks can reveal biological phenomena. Changes among networks in different states influence the direction of living organisms. The identification of the kernel differential subgraph (KDS) that leads to drastic changes is critical. The existing studies contribute to the identification of a KDS in networks with the same nodes; however, networks in different states involve the disappearance of some nodes or the appearance of some new nodes. In this paper, we propose a new topology-based KDS (TKDS) method to explore the core module from gene regulatory networks with different nodes in this process. For the common nodes, the TKDS method considers the differential value (D-value) of the topological change. For the different nodes, TKDS identifies the most similar gene pairs and computes the D-value. Hence, TKDS discovers the essential KDS, which considers the relationships between the same nodes as well as different nodes. After applying this method to non-small cell lung cancer (NSCLC), we identified 30 genes that are most likely related to NSCLC and extracted the KDSs in both the cancer and normal states. Two significance functional modules were revealed, and gene ontology (GO) analyses and literature mining indicated that the KDSs are essential to the processes in NSCLC. In addition, compared with existing methods, TKDS provides a unique perspective in identifying particular genes and KDSs related to NSCLC. Moreover, TKDS has the potential to predict other critical disease-related genes and modules.
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Affiliation(s)
- Jiang Xie
- * School of Computer Engineering and Science, Shanghai University, 99 Shang Da Road, Shanghai 200444, P. R. China
| | - Dongfang Lu
- * School of Computer Engineering and Science, Shanghai University, 99 Shang Da Road, Shanghai 200444, P. R. China
| | - Jiaxin Li
- * School of Computer Engineering and Science, Shanghai University, 99 Shang Da Road, Shanghai 200444, P. R. China
| | - Jiao Wang
- † Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, 99 Shang Da Road, Shanghai 200444, P. R. China
| | - Yong Zhang
- ‡ Pulmonary Department, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
| | - Yanhui Li
- ‡ Pulmonary Department, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, P. R. China
| | - Qing Nie
- § Department of Mathematics, University of California, Irvine, Irvine, California, USA
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41
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Berretta M, Cavaliere C, Alessandrini L, Stanzione B, Facchini G, Balestreri L, Perin T, Canzonieri V. Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications. Oncotarget 2017; 8:14192-14220. [PMID: 28077782 PMCID: PMC5355172 DOI: 10.18632/oncotarget.13929] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022] Open
Abstract
HCC represents the sixth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options for advanced HCC remain limited and unsuccessful, resulting in a poor prognosis. Despite the major advances achieved in the diagnostic management of HCC, only one third of the newly diagnosed patients are presently eligible for curative treatments. Advances in technology and an increased understanding of HCC biology have led to the discovery of novel biomarkers. Improving our knowledge about serum and tissutal markers could ultimately lead to an early diagnosis and better and early treatment strategies for this deadly disease. Serum biomarkers are striking potential tools for surveillance and early diagnosis of HCC thanks to the non-invasive, objective, and reproducible assessments they potentially enable. To date, many biomarkers have been proposed in the diagnosis of HCC. Cholangiocarcinoma (CCA) is an aggressive malignancy, characterized by early lymph node involvement and distant metastasis, with 5-year survival rates of 5%-10%. The identification of new biomarkers with diagnostic, prognostic or predictive value is especially important as resection (by surgery or combined with a liver transplant) has shown promising results and novel therapies are emerging. However, the relatively low incidence of CCA, high frequency of co-existing cholestasis or cholangitis (primary sclerosing cholangitis –PSC- above all), and difficulties with obtaining adequate samples, despite advances in sampling techniques and in endoscopic visualization of the bile ducts, have complicated the search for accurate biomarkers. In this review, we attempt to analyze the existing literature on this argument.
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Affiliation(s)
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto Taranto, Italy
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
| | - Brigida Stanzione
- Department of Medical Oncology, National Cancer Institute, Aviano (PN), Italy
| | - Gaetano Facchini
- Department of Medical Oncology, National Cancer Institute, "G. Pascale" Foundation, Naples, Italy
| | - Luca Balestreri
- Department of Radiology, National Cancer Institute, Aviano (PN), Italy
| | - Tiziana Perin
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
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42
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Ilyas SI, Gores GJ. Emerging molecular therapeutic targets for cholangiocarcinoma. J Hepatol 2017; 67:632-644. [PMID: 28389139 PMCID: PMC5563275 DOI: 10.1016/j.jhep.2017.03.026] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 03/06/2017] [Accepted: 03/24/2017] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation. CCAs are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early-stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis has better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged, including potential driver fibroblast growth factor receptor (FGFR) gene fusions and somatic mutations in isocitrate dehydrogenase (IDH)1/2 in iCCA, protein kinase cAMP-activated catalytic subunit alpha (PRKACA) or beta (PRKACB) gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, the potentially actionable molecular aberrations in each CCA subtype, and the role of immunotherapy in CCA.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Quintavalle C, Burmeister K, Piscuoglio S, Quagliata L, Karamitopoulou E, Sepe R, Fusco A, Terracciano LM, Andersen JB, Pallante P, Matter MS. High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy. Mol Carcinog 2017; 56:2146-2157. [PMID: 28467612 DOI: 10.1002/mc.22671] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 05/01/2017] [Indexed: 12/16/2022]
Abstract
High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has not been addressed yet. Therefore, we determined HMGA1 mRNA expression in CCA samples in a transcriptome array (n = 104) and a smaller cohort (n = 13) by qRT-PCR. Protein expression was evaluated by immunohistochemistry in a tissue microarray (n = 67). In addition, we analyzed changes in cell proliferation, colony formation, response to gemcitabine treatment, and target gene expression after modulation of HMGA1 expression in CCA cell lines. mRNA levels of HMGA1 were found to be upregulated in 15-62% depending on the cohort analyzed. Immunohistochemistry showed HMGA1 overexpression in 51% of CCA specimens. Integration with clinico-pathological data revealed that high HMGA1 expression was associated with reduced time to recurrence and a positive lymph node status in extrahepatic cholangiocellular carcinoma. In vitro experiments showed that overexpression of HMGA1 in CCA cell lines promoted cell proliferation, whereas its suppression reduced growth rate. HMGA1 further promoted colony formation in an anchorage independent growth and conferred resistance to gemcitabine treatment. Finally, HMGA1 modulated the expression of two genes involved in CCA carcinogenesis, iNOS and ERBB2. In conclusion, our findings indicate that HMGA1 expression is increased in a substantial number of CCA specimens. HMGA1 further promotes CCA tumorigenicity and confers resistance to chemotherapy.
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Affiliation(s)
- Cristina Quintavalle
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Katharina Burmeister
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Salvatore Piscuoglio
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Luca Quagliata
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Eva Karamitopoulou
- Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland.,Division of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Romina Sepe
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Alfredo Fusco
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy.,Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Napoli, Italy
| | - Luigi M Terracciano
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Pierlorenzo Pallante
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland.,Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Matthias S Matter
- Division of Molecular Pathology, Institute of Pathology, University of Basel, Basel, Switzerland
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Rahnemai-Azar AA, Weisbrod AB, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: current management and emerging therapies. Expert Rev Gastroenterol Hepatol 2017; 11:439-449. [PMID: 28317403 DOI: 10.1080/17474124.2017.1309290] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify 'target-able' molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients. Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies. Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.
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Affiliation(s)
- Amir A Rahnemai-Azar
- a Department of Surgery , University of Washington Medical Center , Seattle , WA , USA
| | - Allison B Weisbrod
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Mary Dillhoff
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Carl Schmidt
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
| | - Timothy M Pawlik
- b Department of Surgery , The Ohio State University Wexner Medical Center , Columbus , OH , USA
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Oncogenic role of rab escort protein 1 through EGFR and STAT3 pathway. Cell Death Dis 2017; 8:e2621. [PMID: 28230863 PMCID: PMC5386492 DOI: 10.1038/cddis.2017.50] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 12/29/2016] [Accepted: 01/03/2017] [Indexed: 12/20/2022]
Abstract
Rab escort protein-1 (REP1) is linked to choroideremia (CHM), an X-linked degenerative disorder caused by mutations of the gene encoding REP1 (CHM). REP1 mutant zebrafish showed excessive cell death throughout the body, including the eyes, indicating that REP1 is critical for cell survival, a hallmark of cancer. In the present study, we found that REP1 is overexpressed in human tumor tissues from cervical, lung, and colorectal cancer patients, whereas it is expressed at relatively low levels in the normal tissue counterparts. REP1 expression was also elevated in A549 lung cancer cells and HT-29 colon cancer cells compared with BEAS-2B normal lung and CCD-18Co normal colon epithelial cells, respectively. Interestingly, short interfering RNA (siRNA)-mediated REP1 knockdown-induced growth inhibition of cancer cell lines via downregulation of EGFR and inactivation of STAT3, but had a negligible effect on normal cell lines. Moreover, overexpression of REP1 in BEAS-2B cells enhanced cell growth and anchorage-independent colony formation with little increase in EGFR level and STAT3 activation. Furthermore, REP1 knockdown effectively reduced tumor growth in a mouse xenograft model via EGFR downregulation and STAT3 inactivation in vivo. These data suggest that REP1 plays an oncogenic role, driving tumorigenicity via EGFR and STAT3 signaling, and is a potential therapeutic target to control cancers.
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Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C, Pawlik TM. Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. Surg Oncol 2017; 26:125-137. [PMID: 28577718 DOI: 10.1016/j.suronc.2016.12.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/24/2016] [Accepted: 12/29/2016] [Indexed: 02/08/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor with increasing incidence worldwide. The outcome of patients with iCCA is dismal owing to tumor's aggressiveness, late diagnosis and lack of effective treatment options. Detection of the tumor at early stages may make surgical resection, as only potential curative treatment, more feasible. Unfortunately, despite recent developments in imaging modalities and laboratory tests, the diagnosis of iCCA remains challenging and patients often present in advanced stages when surgery cannot be offered. Moreover, accurate assessment of disease burden is critical to optimize management strategy, including the use of adjuvant therapies and clinical trials. Identifying iCCA specific diagnostic and prognostic biomarkers has been a focus of interest among many investigators with a progressive increase in data on iCCA related to advances in "omics" technologies. We herein summarize iCCA biomarkers and define the molecular mechanisms underlying iCCA carcinogenesis, as well as highlight potential diagnostic and prognostic application of molecular biomarkers.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Department of Surgery, University of Washington Medical Center, Seattle, WA, USA
| | - Allison Weisbrod
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Mary Dillhoff
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Carl Schmidt
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
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47
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Rahnemai-Azar AA, Pandey P, Kamel I, Pawlik TM. Monitoring outcomes in intrahepatic cholangiocarcinoma patients following hepatic resection. Hepat Oncol 2017; 3:223-239. [PMID: 30191045 DOI: 10.2217/hep-2016-0009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/04/2016] [Indexed: 02/07/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is one of the fatal gastrointestinal cancers with increasing incidence and mortality. Although surgery offers the only potential for cure in iCCA patients, the prognosis is not optimal with low overall survival rate and high disease recurrence. Hence, adjuvant therapy is generally recommended in the management of high-risk patients. Identifying factors associated with disease recurrence and survival of the iCCA patients after resection will improve understanding of disease prognosis and help in selecting patients who will benefit from surgical resection or stratifying them for clinical trials. Despite development of new methods for early detection of tumor recurrence, effective prognostic models and nomograms, and recent advances in management, significant challenges remain in improving the prognosis of iCCA patients.
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Affiliation(s)
- Amir A Rahnemai-Azar
- Department of Surgery, University of Washington Medical Center, University of Washington School of Medicine, Seattle, WA, USA.,Department of Surgery, University of Washington Medical Center, University of Washington School of Medicine, Seattle, WA, USA
| | - Pallavi Pandey
- Department of Surgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Surgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ihab Kamel
- Department of Radiology, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Radiology, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Timothy M Pawlik
- Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, OH, USA.,Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, OH, USA
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Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. Cholangiocarcinoma. Crit Rev Oncol Hematol 2016; 116:11-31. [PMID: 28693792 DOI: 10.1016/j.critrevonc.2016.11.012] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 11/07/2016] [Accepted: 11/22/2016] [Indexed: 12/15/2022] Open
Abstract
Biliary tract cancer accounts for <1% of all cancers and affects chiefly an elderly population, with predominance in men. We distinguish cholangiocarcinoma (intrahepatic, hilar and distal) and gallbladder cancer, with different pathogenesis and prognosis. The treatment is based on surgery (whenever possible), radiotherapy in selected cases, and chemotherapy. The standard cytotoxic treatment for advanced/metastatic disease is represented by the combination of gemcitabine and cisplatin, whereas fluoropyrimidines are generally administered in second line setting. At the present time, no biologic drug demonstrated a clear efficacy in this cancer, although the molecular characterisation could provide a promising basis for experimental treatments. A good supportive care and an early palliative care are warranted in most patients and should be delivered as a part of a global approach.
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Affiliation(s)
| | - Luca Tondulli
- Medical Oncology Unit, Borgo Roma Hospital, Verona, Italy
| | - Gemma Gatta
- Italian National Cancer Institute, Milan, Italy
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Komposch K, Sibilia M. EGFR Signaling in Liver Diseases. Int J Mol Sci 2015; 17:E30. [PMID: 26729094 PMCID: PMC4730276 DOI: 10.3390/ijms17010030] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
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Affiliation(s)
- Karin Komposch
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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50
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Seeree P, Pearngam P, Kumkate S, Janvilisri T. An Omics Perspective on Molecular Biomarkers for Diagnosis, Prognosis, and Therapeutics of Cholangiocarcinoma. Int J Genomics 2015; 2015:179528. [PMID: 26421274 PMCID: PMC4572471 DOI: 10.1155/2015/179528] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/09/2015] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy arising from the epithelial bile duct. The lack of early diagnostic biomarkers as well as therapeutic measures results in severe outcomes and poor prognosis. Thus, effective early diagnostic, prognostic, and therapeutic biomarkers are required to improve the prognosis and prolong survival rates in CCA patients. Recent advancement in omics technologies combined with the integrative experimental and clinical validations has provided an insight into the underlying mechanism of CCA initiation and progression as well as clues towards novel biomarkers. This work highlights the discovery and validation of molecular markers in CCA identified through omics approaches. The possible roles of these molecules in various cellular pathways, which render CCA carcinogenesis and progression, will also be discussed. This paper can serve as a reference point for further investigations to yield deeper understanding in the complex feature of this disease, potentially leading to better approaches for diagnosis, prognosis, and therapeutics.
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Affiliation(s)
- Pattaya Seeree
- Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Phorutai Pearngam
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Supeecha Kumkate
- Department of Biology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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