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Okano N, Pirozzi A, Abidoye O, Hoyek C, Eslinger C, Zheng-Lin B, Jamal F, Sahwan O, Sonbol MB, Uson Junior PLS, Hayashi M, Sato T, Nishioka M, Nagashima F, Bekaii-Saab T, Borad MJ, Hironaka S. Systemic therapy for pretreated advanced biliary tract cancer: past developments and recent advances. Jpn J Clin Oncol 2025:hyaf052. [PMID: 40173029 DOI: 10.1093/jjco/hyaf052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 03/17/2025] [Indexed: 04/04/2025] Open
Abstract
Biliary tract cancer (BTC) remains among the most challenging malignancies with a poor prognosis and limited treatment options, particularly in pretreated patients. As most patients experience disease progression after first-line treatment, effective second-line and subsequent treatments are required. Although the addition of modified FOLFOX (fluorouracil, leucovorin, and oxaliplatin) to active symptom control improved the overall survival of patients with progressing advanced BTC despite gemcitabine plus cisplatin treatment, its efficacy was modest. Moreover, most clinical trials demonstrated modest efficacy of molecular-targeted agents for molecularly unselected pretreated advanced BTC. Patients with advanced BTC carry a relatively high druggable genetic alteration rate and have shown promising responses to molecular-matched therapies targeting gene alterations such as FGFR2 fusions/rearrangements, IDH1 mutation, and HER2 overexpression/amplification. Additionally, tumor-agnostic approaches, including BRAF V600E, NTRK fusion, and RET fusion, have expanded the treatment options for some patients. Immune checkpoint inhibitors have shown limited efficacy as mono- or combination therapy in patients with pretreated advanced BTC. Therefore, developmental efforts have shifted to immune checkpoint inhibitor and other combinations such as vascular endothelial growth factor receptor inhibitors or radiation. In addition to refining combination strategies to enhance the therapeutic potential of immune checkpoint inhibitor, future research should focus on elucidating the tumor microenvironment. This review delineates the evolution of systemic therapies in patients with pretreated advanced BTC. By examining past developments and recent advances through prospective trials, it highlights novel approaches that may improve outcomes in this challenging disease.
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Affiliation(s)
- Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Angelo Pirozzi
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20072, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan 20089, Italy
| | - Oluseyi Abidoye
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Celine Hoyek
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Cody Eslinger
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Binbin Zheng-Lin
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Fares Jamal
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Oudai Sahwan
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Mohamad Bassam Sonbol
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Pedro Luiz Serrano Uson Junior
- Center for Personalized Medicine, Hospital Israelita Albert Einstein, Avenida Albert Einstein 627, São Paulo 05652900, Brazil
| | - Masato Hayashi
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
| | - Taro Sato
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
- Department of Gastroenterology and Hepatology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
| | - Mariko Nishioka
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
| | - Tanios Bekaii-Saab
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Mitesh J Borad
- Division of Hematology and Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054, United States
| | - Shuichi Hironaka
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
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Hossain MA. A comprehensive review of targeting RAF kinase in cancer. Eur J Pharmacol 2025; 986:177142. [PMID: 39577552 DOI: 10.1016/j.ejphar.2024.177142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/11/2024] [Accepted: 11/17/2024] [Indexed: 11/24/2024]
Abstract
RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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Areewong S, Suppramote O, Prasopporn S, Jirawatnotai S. Exploiting acquired vulnerability to develop novel treatments for cholangiocarcinoma. Cancer Cell Int 2024; 24:362. [PMID: 39501277 PMCID: PMC11539612 DOI: 10.1186/s12935-024-03548-2] [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: 07/14/2024] [Accepted: 10/26/2024] [Indexed: 11/08/2024] Open
Abstract
Cholangiocarcinoma (CCA) presents a formidable therapeutic challenge due to its extensive heterogeneity and plasticity, which inevitably lead to acquired resistance to current treatments. However, recent evidence suggests that acquired drug resistance is associated with a fitness cost resulting from the myriad of acquired alterations under the selective pressure of the primary treatment. Consequently, CCA patients with acquired resistance are more susceptible to alternative therapies that are ineffective as monotherapies. This phenomenon, termed "acquired vulnerability," has garnered significant interest in drug development, as the acquired alterations could potentially be exploited therapeutically. This review elucidates the modes of acquired vulnerability, methods for identifying and exploiting acquired vulnerabilities in cancer (particularly in CCA), and strategies to enhance the clinical efficacy of drug combinations by leveraging the principle of acquired vulnerability. Identifying acquired vulnerabilities may pave the way for novel drug combinations to effectively treat highly heterogeneous and adaptable malignancies such as CCA.
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Affiliation(s)
- Sirayot Areewong
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., 11th Floor Srisavarindhira Building, Bangkok Noi, 10700, Bangkok, Thailand
| | - Orawan Suppramote
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, 906 Kampangpetch 6 Rd., Talat Bang Khen, Lak Si, 10210, Bangkok, Thailand
| | - Sunisa Prasopporn
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., 11th Floor Srisavarindhira Building, Bangkok Noi, 10700, Bangkok, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center of Research Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., 11th Floor Srisavarindhira Building, Bangkok Noi, 10700, Bangkok, Thailand.
- Faculty of Pharmacy, Silpakorn University, 6 Ratchamankanai Road., Phra Pathom Chedi Sub-district, Mueang District, 73000, Nakhon Pathom, Thailand.
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Asensio M, Briz O, Herraez E, Perez-Silva L, Espinosa-Escudero R, Bueno-Sacristan D, Peleteiro-Vigil A, Hammer H, Pötz O, Kadioglu O, Banales JM, Martinez-Chantar ML, Avila MA, Macias RIR, Efferth T, Marin JJG, Lozano E. Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3. Biomed Pharmacother 2024; 180:117533. [PMID: 39405909 DOI: 10.1016/j.biopha.2024.117533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/25/2024] [Accepted: 10/04/2024] [Indexed: 11/14/2024] Open
Abstract
AIMS Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance. METHODS Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo. RESULTS High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin. CONCLUSIONS Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.
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Affiliation(s)
- Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | - Laura Perez-Silva
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | | | - Diego Bueno-Sacristan
- Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Service of Pathology, University Hospital of Salamanca, Salamanca, Spain
| | - Ana Peleteiro-Vigil
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain
| | | | - Oliver Pötz
- Signatope GmbH, Reutlingen, Germany; Natural and Medical Sciences Institute at the University of Tubingen (NMI), Reutlingen, Germany
| | - Onat Kadioglu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Jesus M Banales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain; Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Maria L Martinez-Chantar
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain; Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CICbioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
| | - Matias A Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain; Hepatology Laboratory, Solid Tumors Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Rocio I R Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain.
| | - Elisa Lozano
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Salamanca, Spain; Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma. Cancers (Basel) 2024; 16:1690. [PMID: 38730642 PMCID: PMC11083102 DOI: 10.3390/cancers16091690] [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: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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Amonkar MM, Abderhalden LA, Fox GE, Frederickson AM, Grira T, Gozman A, Malhotra U, Malbecq W, Akers KG. Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis. Future Oncol 2024; 20:863-876. [PMID: 38353044 DOI: 10.2217/fon-2023-0006] [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: 01/03/2023] [Accepted: 01/30/2024] [Indexed: 03/27/2024] Open
Abstract
Aim: A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Materials & methods: Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were calculated using random effects meta-analysis. Results: Across 31 studies evaluating chemotherapy or targeted treatment regimens in an unselected advanced BTC patient population, pooled ORR was 6.9%, median OS was 6.6 months and median PFS was 3.2 months. Conclusion: The efficacy of conventional treatments for previously treated advanced BTC patients is poor and could be improved by novel therapies.
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Myint KZ, Sueca-Comes M, Collier P, Balasubramanian B, Venkatraman S, Gordan J, Zaitoun AM, Mukherjee A, Arora A, Larbcharoensub N, Suriyonplengsaeng C, Wongprasert K, Janvilisri T, Gomez D, Grabowska AM, Tohtong R, Bates DO, Yacqub-Usman K. Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma. Front Oncol 2023; 13:1184900. [PMID: 38144528 PMCID: PMC10748508 DOI: 10.3389/fonc.2023.1184900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 11/06/2023] [Indexed: 12/26/2023] Open
Abstract
Introduction Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. Methods ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. Results ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. Discussion These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.
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Affiliation(s)
- Kyaw Zwar Myint
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Mireia Sueca-Comes
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Pamela Collier
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Brinda Balasubramanian
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Simran Venkatraman
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - John Gordan
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Abed M. Zaitoun
- Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Abhik Mukherjee
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Arvind Arora
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
- Department of Medical Oncology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom
| | - Noppadol Larbcharoensub
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Dhanny Gomez
- Department of Hepatobiliary and Pancreatic Surgery, and National Institute of Health Care Research (NIHR) Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom
| | - Anna M. Grabowska
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - David O. Bates
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
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Romanzi A, Villa E. Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma. HEPATOMA RESEARCH 2023. [DOI: 10.20517/2394-5079.2023.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.
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Serrano Uson Junior PL, Bekaii-Saab T. Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? Immunotherapy 2023; 15:531-540. [PMID: 37096922 DOI: 10.2217/imt-2022-0201] [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: 04/26/2023] Open
Abstract
Background: Immunotherapy has been shown to improve outcomes for patients with cancer. Biliary tract cancers are a group of lethal diseases, and immunotherapy is an exciting new strategy to treat patients in advanced stages. Role of immunotherapy in biliary cancers: Durvalumab, an anti-PD-L1 antibody, is a new immunotherapy option for patients with advanced biliary cancers. In a randomized phase III trial, the combination of durvalumab and chemotherapy improved disease outcomes, including overall survival, in patients with advanced biliary cancers regardless of PD-L1 expression. Future perspective: Promising new combinations with new and potent antibodies or antiangiogenics are under development. Combinations with new immunotherapy agents targeting CTLA-4 or OX40 can enhance T-cell activation and improve outcomes compared with single anti-PD-1/PD-L1 agents. Furthermore, ctDNA is being used as an alternative to tissue genomic analysis and can be used to identify actionable targets. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.
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Du J, Lv X, Zhang Z, Huang Z, Zhang E. Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma. Front Immunol 2023; 14:1142690. [PMID: 36936931 PMCID: PMC10014562 DOI: 10.3389/fimmu.2023.1142690] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare and aggressive type of malignant tumor. In the past few years, there has been an increase in the incidence of CCA. Surgery is the only effective treatment but is only suitable for a small percentage of patients. Comprehensive treatment is the normal therapy for terminal CCA patients, depending basically on gemcitabine and cisplatin combination chemotherapy. In the past decade, the emergence of next-generation sequencing technology can be used for the identification of important molecular features of CCA, and several studies have demonstrated that different CCA subtypes have unique genetic aberrations. Targeting fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH) and epidermal growth factor receptor 2 (EGFR2) are emerging targeted therapies. In addition, researches have indicated that immunotherapy has a key function in CCA. There is ongoing research on programmed cell death protein 1 inhibitors (PD-1), chimeric antigen receptor T cells (CAR-T) and tumor-infiltrating leukocyte (TILs). Researches have shown that targeted therapy, immunotherapy, and conventional chemotherapy in CCA had certain mechanistic links, and the combination of those can greatly improve the prognosis of advanced CCA patients. This study aimed to review the research progress of targeted therapy and immunotherapy for CCA.
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Affiliation(s)
| | | | | | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Erlei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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11
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Yang M, Zhao Y, Li Y, Cui X, Liu F, Wu W, Wang XA, Li M, Liu Y, Liu Y. Afatinib in combination with GEMOX chemotherapy as the adjuvant treatment in patients with ErbB pathway mutated, resectable gallbladder cancer: study protocol for a ctDNA-based, multicentre, open-label, randomised, controlled, phase II trial. BMJ Open 2023; 13:e061892. [PMID: 36854604 PMCID: PMC9980349 DOI: 10.1136/bmjopen-2022-061892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
INTRODUCTION Gallbladder cancer (GBC) is an aggressive type of digestive system cancer with a dismal outcome. Given the lack of effective treatment options, the disease rapidly reoccurs and 5-year survival rate is <5%. Our team previously found that a significant percentage of GBC tissues harboured mutations of the ErbB-related pathway. Afatinib is a chemically synthesised drug specifically targeting the ErbB pathway mutations. However, its efficacy in the treatment of patients with GBC remains unknown. Circulating tumour DNA (ctDNA) refers to a proportion of cell-free DNA in the blood which is released by apoptotic and necrotic cells from tumours in situ, metastatic foci or circulating tumour cells. ctDNA-based liquid biopsy is a non-invasive pathological detection method that offers additional value to evaluate the therapeutic efficacy of antitumour drugs. METHODS AND ANALYSIS We conduct a multicentre and randomised study on afatinib combined with gemcitabine and oxaliplatin (GEMOX) in patients with ErbB pathway mutated GBC. Clinical and biological evaluation involving ErbB pathway ctDNA detection will be made during the 3-year follow-up after participation. The primary objective of this clinical trial is to evaluate the clinical efficacy of afatinib. Disease-free survival is the primary end point and will be correlated with plasma ctDNA of patients in the treatment with afatinib. In addition, we will evaluate the sensitivity and specificity of plasma ctDNA for monitoring tumour recurrence and progression. Finally, we will assess the safety of afatinib by keeping an eye on the safety indicators. ETHICS AND DISSEMINATION The study was approved by the medical-ethical review committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The clinical trials results, even inconclusive, will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT04183712.
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Affiliation(s)
- Mao Yang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yuhao Zhao
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yongsheng Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xuya Cui
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Fatao Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Wenguang Wu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Xu-An Wang
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yun Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, Shanghai, China
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12
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Sturm N, Schuhbaur JS, Hüttner F, Perkhofer L, Ettrich TJ. Gallbladder Cancer: Current Multimodality Treatment Concepts and Future Directions. Cancers (Basel) 2022; 14:5580. [PMID: 36428670 PMCID: PMC9688543 DOI: 10.3390/cancers14225580] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Gallbladder cancer (GBC) is the most common primary tumor site of biliary tract cancer (BTC), accounting for 0.6% of newly diagnosed cancers and 0.9% of cancer-related deaths. Risk factors, including female sex, age, ethnic background, and chronic inflammation of the gallbladder, have been identified. Surgery is the only curative option for early-stage GBC, but only 10% of patients are primary eligible for curative treatment. After neoadjuvant treatment, up to one-third of locally advanced GBC patients could benefit from secondary surgical treatment. After surgery, only a high-risk subset of patients benefits from adjuvant treatment. For advanced-stage GBC, palliative chemotherapy with gemcitabine and cisplatin is the current standard of care in line with other BTCs. After the failure of gemcitabine and cisplatin, data for second-line treatment in non-resectable GBC is poor, and the only recommended chemotherapy regimen is FOLFOX (5-FU/folinic acid and oxaliplatin). Recent advances with the PD-L1 inhibitor durvalumab open the therapy landscape for immune checkpoint inhibition in GBC. Meanwhile, targeted therapy approaches are a cornerstone of GBC therapy based on molecular profiling and new evidence of molecular differences between different BTC forms and might further improve the prognosis of GBC patients.
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Affiliation(s)
- Niklas Sturm
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
| | | | - Felix Hüttner
- Department of General and Visceral Surgery, Ulm University Hospital, 89081 Ulm, Germany
| | - Lukas Perkhofer
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
| | - Thomas Jens Ettrich
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany
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13
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Cadamuro M, Romanzi A, Guido M, Sarcognato S, Cillo U, Gringeri E, Zanus G, Strazzabosco M, Simioni P, Villa E, Fabris L. Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma. J Pers Med 2022; 12:jpm12071086. [PMID: 35887583 PMCID: PMC9324584 DOI: 10.3390/jpm12071086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/23/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.
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Affiliation(s)
| | - Adriana Romanzi
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, 41124 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (M.G.); (S.S.)
- Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy;
| | - Samantha Sarcognato
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy; (M.G.); (S.S.)
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Enrico Gringeri
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Giacomo Zanus
- Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35122 Padua, Italy; (U.C.); (E.G.); (G.Z.)
| | - Mario Strazzabosco
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale University, New Haven, CT 208056, USA;
| | - Paolo Simioni
- Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy;
- General Internal Medicine Unit, Padua University-Hospital, 35122 Padua, Italy
| | - Erica Villa
- Gastroenterology Unit, Department of Medical Specialties, University of Modena & Reggio Emilia and Modena University-Hospital, 41124 Modena, Italy;
- Correspondence: (E.V.); (L.F.); Tel.: +39-059-422-5308 (E.V.); +39-049-821-3131 (L.F.); Fax: +39-059-422-4424 (E.V.); +39-049-827-2355 (L.F.)
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, 35122 Padua, Italy;
- Liver Center, Digestive Disease Section, Department of Internal Medicine, Yale University, New Haven, CT 208056, USA;
- General Internal Medicine Unit, Padua University-Hospital, 35122 Padua, Italy
- Correspondence: (E.V.); (L.F.); Tel.: +39-059-422-5308 (E.V.); +39-049-821-3131 (L.F.); Fax: +39-059-422-4424 (E.V.); +39-049-827-2355 (L.F.)
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14
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Chen W, Hu Z, Song J, Wu Y, Zhang B, Zhang L. The state of therapy modalities in clinic for biliary tract cancer. FRONT BIOSCI-LANDMRK 2022; 27:185. [PMID: 35748261 DOI: 10.31083/j.fbl2706185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 11/06/2022]
Abstract
Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (iCCA), perihilar and distal cholangiocarcinoma (pCCA and dCCA), and gallbladder carcinoma based on the epithelial site of origin. BTCs are highly aggressive tumors associated with poor prognosis due to widespread metastasis and high recurrence. Surgery is the typical curative-intent treatment, yet the cornerstone of cure depends on the anatomical site of the primary tumor, and only a minority of patients (approximately 30%) has an indication necessitating surgery. Similarly, only a small subset of carefully selected patients with early iCCA who are not candidates for liver resection can opt for liver transplantation. Chemotherapy, target therapy, and immunotherapy are the main treatment options for patients who have advanced stage or unresectable disease. The genetic background of each cholangiocarcinoma subtype has been accurately described based on whole gene exome and transcriptome sequencing. Accordingly, precision medicine in targeted therapies has been identified to be aimed at distinct patient subgroups harboring unique molecular alterations. Immunotherapy such as immune checkpoint inhibitors (ICIs) was identified as antitumor responses in a minority of select patients. Current studies indicate that immunotherapy of adoptive cell therapy represents a promising approach in hematological and solid tumor malignancies, yet clinical trials are needed to validate its effectiveness in BTC. Herein, we review the progress of BTC treatment, stratified patients according to the anatomic subtypes of cholangiocarcinoma and the gene drivers of cholangiocarcinoma progression, and compare the efficacy and safety of chemotherapy, targeted therapy, and immunotherapy, which will be conducive to the design of individualized therapies.
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Affiliation(s)
- Weixun Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Zhengnan Hu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Jia Song
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Yu Wu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Bixiang Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Lei Zhang
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 030032 Taiyuan, Shanxi, China
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15
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Swetha M, Keerthana CK, Rayginia TP, Nath LR, Haritha NH, Shabna A, Kalimuthu K, Thangarasu AK, Aiswarya SU, Jannet S, Pillai S, Harikumar KB, Sundaram S, Anto NP, Wu DH, Lankalapalli RS, Towner R, Isakov N, Deepa SS, Anto RJ. Augmented Efficacy of Uttroside B over Sorafenib in a Murine Model of Human Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2022; 15:636. [PMID: 35631464 PMCID: PMC9143354 DOI: 10.3390/ph15050636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/21/2022] [Accepted: 04/30/2022] [Indexed: 12/03/2022] Open
Abstract
We previously reported the remarkable potency of uttroside B (Utt-B), saponin-isolated and characterized in our lab from Solanum nigrum Linn, against HCC. Recently, the U.S. FDA approved Utt-B as an 'orphan drug' against HCC. The current study validates the superior anti-HCC efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. The therapeutic efficacies of Utt-B vs. sorafenib against HCC were compared in vitro, using various liver cancer cell lines and in vivo, utilizing NOD.CB17-Prkdcscid/J mice bearing human HCC xenografts. Our data indicate that Utt-B holds an augmented anti-HCC efficacy over sorafenib. Our previous report demonstrated the pharmacological safety of Utt-B in Chang Liver, the normal immortalized hepatocytes, and in the acute and chronic toxicity murine models even at elevated Utt-B concentrations. Here, we show that higher concentrations of sorafenib induce severe toxicity, in Chang Liver, as well as in acute and chronic in vivo models, indicating that, apart from the superior therapeutic benefit over sorafenib, Utt-B is a pharmacologically safer molecule, and the drug-induced undesirable effects can, thus, be substantially alleviated in the context of HCC chemotherapy. Clinical studies in HCC patients utilizing Utt-B, is a contiguous key step to promote this drug to the clinic.
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Affiliation(s)
- Mundanattu Swetha
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
- Department of Biotechnology, University of Kerala, Thiruvananthapuram 695011, Kerala, India
| | - Chenicheri K. Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
- Department of Biotechnology, University of Kerala, Thiruvananthapuram 695011, Kerala, India
| | - Tennyson P. Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
- Department of Biotechnology, University of Kerala, Thiruvananthapuram 695011, Kerala, India
| | - Lekshmi R. Nath
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India
| | - Nair Hariprasad Haritha
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Anwar Shabna
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Kalishwaralal Kalimuthu
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Arun K. Thangarasu
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India; (A.K.T.); (R.S.L.)
| | - Sreekumar U. Aiswarya
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Somaraj Jannet
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Sreekumar Pillai
- Department of Surgical Oncology, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India;
| | - Kuzhuvelil B. Harikumar
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
| | - Sankar Sundaram
- Department of Pathology, Government Medical College, Kottayam 686008, Kerala, India;
| | - Nikhil Ponnoor Anto
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel; (N.P.A.); (N.I.)
| | - Dee H. Wu
- Section of Medical Physics, Department of Radiological Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
- School of Computer Science, Gallogly College of Engineering, University of Oklahoma, Norman, OK 731019, USA
- School of Electrical and Computer Engineering, Gallogly College of Engineering, University of Oklahoma, Norman, OK 731019, USA
| | - Ravi S. Lankalapalli
- Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India; (A.K.T.); (R.S.L.)
| | - Rheal Towner
- Departments of Pathology and Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Noah Isakov
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel; (N.P.A.); (N.I.)
| | - Sathyaseelan S. Deepa
- Department of Biochemistry and Molecular Biology, and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; (M.S.); (C.K.K.); (T.P.R.); (L.R.N.); (N.H.H.); (A.S.); (K.K.); (S.U.A.); (S.J.); (K.B.H.)
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Gray S, Lamarca A, Edeline J, Klümpen HJ, Hubner RA, McNamara MG, Valle JW. Targeted Therapies for Perihilar Cholangiocarcinoma. Cancers (Basel) 2022; 14:1789. [PMID: 35406560 PMCID: PMC8997784 DOI: 10.3390/cancers14071789] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.
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Affiliation(s)
- Simon Gray
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Julien Edeline
- Centre Eugène Marquis, Av. de la Bataille Flandres Dunkerque-CS 44229, CEDEX, 35042 Rennes, France;
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Center, P.O. Box 7057, 1081 HV Amsterdam, The Netherlands;
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK; (S.G.); (A.L.); (R.A.H.); (M.G.M.)
- Division of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL, UK
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Kang S, El-Rayes BF, Akce M. Evolving Role of Immunotherapy in Advanced Biliary Tract Cancers. Cancers (Basel) 2022; 14:1748. [PMID: 35406520 PMCID: PMC8996885 DOI: 10.3390/cancers14071748] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancers (BTC) comprise a rare and diverse group of malignancies that involve the gallbladder and biliary tree. These cancers typically present in later stages because they are aggressive in nature and affected patients are often asymptomatic in earlier stages of disease. Moreover, BTCs are generally refractory to cytotoxic chemotherapy, which further contributes to their associated poor survival outcomes. Novel therapy approaches are clearly needed. Molecular targeted agents have been developed based on our expanding knowledge of the genetic mutations underlying BTCs and represent a promising treatment strategy in molecularly selected subgroups of patients. In addition, the advent of immunotherapy over recent years has dramatically changed the bleak outcomes observed in malignancies such as melanoma. Our growing understanding of the complex tumor microenvironment in BTC has identified mechanisms of tumor immune evasion that could potentially be targeted with immunotherapy. As a result, different immunotherapeutic approaches including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, have been investigated. The use of immunotherapeutic agents is currently only approved for a small subset of treatment-refractory BTCs based on microsatellite instability (MSI) status and tumor mutational burden (TMB), but this will likely change with the potential approval of immunotherapy plus chemotherapy as a result of the TOPAZ-1 trial.
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Affiliation(s)
- Sandra Kang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA;
| | - Bassel F. El-Rayes
- Department of Internal Medicine, Division of Hematology and Oncology, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA;
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA;
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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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Rimini M, Puzzoni M, Pedica F, Silvestris N, Fornaro L, Aprile G, Loi E, Brunetti O, Vivaldi C, Simionato F, Zavattari P, Scartozzi M, Burgio V, Ratti F, Aldrighetti L, Cascinu S, Casadei-Gardini A. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021; 15:1367-1383. [PMID: 34669536 DOI: 10.1080/17474124.2021.1991313] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. AREA COVERED In the last years, a growing interest in BTC pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations, which may have an interesting clinical application in the next future. EXPERT OPINION In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures, including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Puzzoni
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Federica Pedica
- Department of Pathology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Silvestris
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.,Department of Biomedical Sciences and Human Oncology, Aldo Moro University of Bari, Bari, Italy
| | - Lorenzo Fornaro
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Oronzo Brunetti
- Department of oncology, Instituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy
| | - Caterina Vivaldi
- Department of medical oncology, U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Francesca Simionato
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology, University and University Hospital of Cagliari, Italy
| | - Valentina Burgio
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Francesca Ratti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele and Vita-Salute University, Italy
| | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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20
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Aimar G, Paratore C, Zichi C, Marino D, Sperti E, Caglio A, Gamba T, De Vita F, Di Maio M. A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:448-464. [PMID: 36045702 PMCID: PMC9400771 DOI: 10.37349/etat.2021.00056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.
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Affiliation(s)
- Giacomo Aimar
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Chiara Paratore
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Donatella Marino
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Elisa Sperti
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Andrea Caglio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Teresa Gamba
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Francesca De Vita
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy
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21
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Wang Y, Chen T, Li K, Mu W, Liu Z, Shi A, Liu J, Zhao W, Lian S, Huang S, Pan C, Zhang Z. Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer. Front Oncol 2021; 11:777617. [PMID: 34778094 PMCID: PMC8581488 DOI: 10.3389/fonc.2021.777617] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/11/2021] [Indexed: 12/25/2022] Open
Abstract
Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.
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Affiliation(s)
- Yue Wang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianli Chen
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Kangshuai Li
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wentao Mu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jialiang Liu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Zhao
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuo Lian
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chang Pan
- Department of Emergency, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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22
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Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. Lancet Gastroenterol Hepatol 2021; 6:956-969. [PMID: 34626563 DOI: 10.1016/s2468-1253(21)00171-0] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023]
Abstract
Biliary tract cancers (cholangiocarcinomas and gallbladder cancers) are increasing in incidence and have a poor prognosis. Most patients present with advanced disease, for which the treatment is palliative chemotherapy. Over the past few years, the genomic landscape of biliary tract cancers has been examined and several targeted therapies have been developed. Molecular targets with clinically meaningful activity include fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), RAS-RAF-MEK (MAP2K1)-ERK (MAPK3), HER2 (also known as ERBB2), DNA mismatch repair, and NTRK. Pemigatinib, a FGFR1-3 inhibitor, showed encouraging response rates and survival data as second-line treatment and received US Food and Drug Administration (FDA) approval in April, 2020, for previously treated advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangements. Ivosidenib, an IDH1 inhibitor, showed improved progression-free survival versus placebo in second-line treatment in the phase 3 ClarIDHy trial. Early phase trials of dabrafenib plus trametinib (BRAF and MEK inhibition) and zanidatamab (a bispecific HER2-antibody) have yielded encouraging response rates. Immunotherapy has mainly produced responses in tumours with deficient mismatch repair or high microsatellite instability (also known as dMMR or MSI-H) or higher PD-L1 score, or both. However, early phase trials of immunotherapy plus chemotherapy in unselected patient populations appear promising. NTRK inhibitors have also shown promise in early phase trials of NTRK-fusion positive solid tumours, including cholangiocarcinoma. In this Review, we discuss current and emerging therapies for advanced biliary tract cancers, with a focus on molecularly targeted therapy.
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Affiliation(s)
- Audrey E Kam
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA.
| | - Ashiq Masood
- Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL, USA
| | - Rachna T Shroff
- Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ, USA
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23
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Wang C, Huang M, Geng Q, Li W, Chang J, Tang W, Guo W. Apatinib for patients with metastatic biliary tract carcinoma refractory to standard chemotherapy: results from an investigator-initiated, open-label, single-arm, exploratory phase II study. Ther Adv Med Oncol 2021; 13:17588359211039047. [PMID: 34484431 PMCID: PMC8411636 DOI: 10.1177/17588359211039047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND There is no standard therapy for metastatic biliary tract carcinoma (BTC) refractory to first-line chemotherapy. Apatinib, a VEGFR2 tyrosine kynase inhibitor, showed an activity against BTC xenografts in preclinical models. We conducted an exploratory study to evaluate the efficacy and safety of apatinib in patients with metastatic BTC. METHODS This is a single-arm phase II study [ClinicalTrials.gov identifier: NCT03427242]. Eligible patients were aged 18 years or older; histologically confirmed metastatic BTC; refractory or intolerance to at least one chemotherapeutic regimen; no prior use of anti-angiogenic targeted drugs; Eastern Cooperative Oncology Group performance status of 0-2. Patients received oral apatinib 500 mg each day continuously until unacceptable toxicity or tumor progression. The primary endpoint was progress free survival (PFS). The secondary endpoint was overall survival (OS), objective response rate (ORR) and treatment safety. RESULTS A total of 22 patients were recruited. All of them received apatinib medication. The median age was 63 (44-75) years old. Twenty patients received efficacy evaluation after treatment. The objective response rate (ORR) and disease control rate (DCR) were 15.0% and 60.0%, respectively. The median PFS was 2.73 months [95% confidence interval (CI): 1.74-3.72 months], with 6 months PFS rate of 27.3% (95% CI: 8.7-45.9%). The median OS was 4.81 months (95% CI: 3.16-10.9 months), with 12 months OS rate of 36.4% (95% CI: 16.2-56.6%). Nine out of 22 patients (40.9%) had grade 3/4 adverse events. The most common grade 3/4 adverse events were hand-foot skin syndrome [three (13.6%) patients] and hypertension [two (9.1%) patients]. No treatment-related death occurred. CONCLUSIONS For patients with metastatic BTC, apatinib showed an anti-tumor activity with acceptable safety, which deserves the further clinical trial.This trial was prospectively registered on ClinicalTrials.gov [NCT03427242]. Date of first patient enrollment: 26 January 2018. Date of registration (date of first posted): 9 February 2018.
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Affiliation(s)
- Chenchen Wang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Qirong Geng
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Wenhua Li
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Jinjia Chang
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Wei Tang
- Department of Radiology, Fudan University
Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical
College, Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai Medical College, Shanghai
200032, China
- Department of Radiology, Fudan University
Shanghai Cancer Center, Shanghai, China
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24
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Maier CF, Zhu L, Nanduri LK, Kühn D, Kochall S, Thepkaysone ML, William D, Grützmann K, Klink B, Betge J, Weitz J, Rahbari NN, Reißfelder C, Schölch S. Patient-Derived Organoids of Cholangiocarcinoma. Int J Mol Sci 2021; 22:ijms22168675. [PMID: 34445380 PMCID: PMC8395494 DOI: 10.3390/ijms22168675] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/03/2021] [Accepted: 08/07/2021] [Indexed: 12/16/2022] Open
Abstract
Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.
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Affiliation(s)
- Christopher Fabian Maier
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Lei Zhu
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Lahiri Kanth Nanduri
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Daniel Kühn
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Susan Kochall
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - May-Linn Thepkaysone
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Doreen William
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Konrad Grützmann
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Barbara Klink
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (K.G.); (B.K.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- National Center of Genetics, Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
| | - Johannes Betge
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models (B440), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
- Department of Medicine II, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (L.K.N.); (D.K.); (S.K.); (M.-L.T.); (J.W.)
| | - Nuh N. Rahbari
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Christoph Reißfelder
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
| | - Sebastian Schölch
- Junior Clinical Cooperation Unit Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (C.F.M.); (L.Z.)
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, 68167 Mannheim, Germany; (N.N.R.); (C.R.)
- Correspondence:
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Xu J, Bai Y, Sun H, Bai C, Jia R, Li Y, Zhang W, Liu L, Huang C, Guan M, Zhou J, Su W. A single-arm, multicenter, open-label phase 2 trial of surufatinib in patients with unresectable or metastatic biliary tract cancer. Cancer 2021; 127:3975-3984. [PMID: 34355801 DOI: 10.1002/cncr.33803] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/30/2021] [Accepted: 05/14/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Several clinical studies of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) therapy as a second-line treatment for biliary tract cancer (BTC) have shown modest efficacy. In this study, surufatinib was evaluated as a second-line VEGFR therapy in patients with BTC. METHODS This was a single-arm, multicenter, open-label phase 2 study conducted in China. The study enrolled eligible patients with BTC, who had received surufatinib monotherapy as second-line treatment, at a dose of 300 mg, once daily, in 28-day cycles. Tumor assessments were performed every 8 weeks (±7 days) according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS As of November 30, 2018, 39 patients with BTC, including 29 (74.4%) with intrahepatic cholangiocarcinoma, 5 (12.8%) with extrahepatic cholangiocarcinoma, and 5 (12.8%) with gallbladder cancer, were enrolled and treated with surufatinib. The 16-week progression-free survival rate was 46.33% (95% CI, 24.38-65.73), with median progression-free survival of 3.7 months and median overall survival of 6.9 months. In addition, results from subgroup and post hoc analyses revealed that patients with the proper tumor locations or appropriate levels of serum biomarkers might receive greater clinical benefits. The top 3 treatment-related adverse events with severity of grade ≥3 included blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). CONCLUSIONS When applied in the treatment of patients with BTC, surufatinib monotherapy has offered moderate clinical efficacy and shown expected tolerability and safety profiles.
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Affiliation(s)
- Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center, General Hospital of the People's Liberation Army, Beijing, China
| | - Yuxian Bai
- Department of Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Huichuan Sun
- Department of Liver Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunmei Bai
- Department of Oncology, Chinese Academy of Medical Science & Peking Union Medical College Hospital, Beijing, China
| | - Ru Jia
- Department of Gastrointestinal Oncology, The Fifth Medical Center, General Hospital of the People's Liberation Army, Beijing, China
| | - Yi Li
- Department of Gastrointestinal Oncology, The Fifth Medical Center, General Hospital of the People's Liberation Army, Beijing, China
| | - Wenjie Zhang
- Department of Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Lei Liu
- Department of Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Cheng Huang
- Department of Liver Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mei Guan
- Department of Oncology, Chinese Academy of Medical Science & Peking Union Medical College Hospital, Beijing, China
| | - Jinghong Zhou
- Clinical Development and Regulatory Affairs, Hutchison MediPharma, Shanghai, China
| | - Weiguo Su
- Clinical Development and Regulatory Affairs, Hutchison MediPharma, Shanghai, China
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Significant Response to Camrelizumab Plus Targeted Drugs in Recurrent Intrahepatic Cholangiocarcinoma: a Case Report and Literature Review. J Gastrointest Cancer 2021; 53:817-824. [PMID: 34312770 PMCID: PMC9436883 DOI: 10.1007/s12029-021-00637-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2021] [Indexed: 11/19/2022]
Abstract
Purpose Intrahepatic cholangiocarcinoma is the second most common primary liver cancer, and is associated with a poor prognosis and rising incidence rate. Methods Here, we reported the case of a middle-aged Asian male who presented with a 9.5-cm liver lesion and was diagnosed with intrahepatic cholangiocarcinoma. Results The patient experienced recurrence three times, twice following radical resection and standard adjuvant chemotherapy and once following camrelizumab plus apatinib, after which the tumor progressed with elevated CA 19.9 level. After tissue biopsy for next-generation sequencing, apatinib was replaced by lenvatinib, and the patient achieved disease control again, with a progression-free survival of 10 months. Conclusion Combined immunotherapy and targeted therapy regimens are a promising approach for refractory intrahepatic cholangiocarcinoma. Further well-designed prospective clinical trials are needed to confirm the efficacy and safety. Since intrahepatic cholangiocarcinoma is characterized by high heterogeneity and with complex crosstalk among oncogenic pathways, further exploration is required to more deeply understand the mechanism of action of this treatment approach and guide individualized treatment selection.
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De Lorenzo S, Garajova I, Stefanini B, Tovoli F. Targeted therapies for gallbladder cancer: an overview of agents in preclinical and clinical development. Expert Opin Investig Drugs 2021; 30:759-772. [PMID: 33966562 DOI: 10.1080/13543784.2021.1928636] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023]
Abstract
Introduction: Gallbladder cancer (GC) is a rare malignancy with a dismal prognosis. When diagnosed early enough, it can be cured by surgical removal. Unfortunately, only few GC patients can be amenable to surgery, though, with a high relapse rate. Conventional chemotherapy remains the golden standard for unresectable or metastatic GC, both in the first and second-line settings, even if leading to a fair outcome improvement.Areas covered: In recent years, according to the concept of 'precision medicine', new potential molecular targets have been examined. We provided a general outline of the current first- and second-line chemotherapies. New therapeutic possibilities are also reviewed, particularly HER2, EGFR, VEGF, TKI, MEK and BRAF inhibitors, and immunotherapy. Furthermore, published clinical trials are utilized to analyze the principal drug effectiveness in GC.Expert opinion: GC is characterized by vast cancer heterogeneity and individual's efficacy to different drugs. The ongoing trials have the potentiality of reshaping the landscape of systemic treatments for GC in the very next years. Nowadays, amongst therapeutic combinations, the addition of ICIs to chemotherapy has yielded encouraging results needing confirmation. In the next future, systematic implementation of gene profiling and further explorations of combination therapies will likely change the treatment scenario.
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Affiliation(s)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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Wang Y, Yu H, Xie X, Deng T, Ye L, Wu L, Ding X, Yang Z, Zhu Q, Li J, Zheng Y, Yu Z, Chen G. Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway. Oncogene 2021; 40:4324-4337. [PMID: 34079085 DOI: 10.1038/s41388-021-01844-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 04/26/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.
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Affiliation(s)
- Yi Wang
- Division of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
| | - Haitao Yu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozai Xie
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Tuo Deng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Longyun Ye
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lijun Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiwei Ding
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Qiandong Zhu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Junjian Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yihu Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhengping Yu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Yao WY, Gong W. Immunotherapy in cholangiocarcinoma: From concept to clinical trials. SURGERY IN PRACTICE AND SCIENCE 2021; 5:100028. [DOI: 10.1016/j.sipas.2021.100028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Kamp EJCA, Dinjens WNM, Doukas M, Bruno MJ, de Jonge PJF, Peppelenbosch MP, de Vries AC. Optimal tissue sampling during ERCP and emerging molecular techniques for the differentiation of benign and malignant biliary strictures. Therap Adv Gastroenterol 2021; 14:17562848211002023. [PMID: 33948111 PMCID: PMC8053835 DOI: 10.1177/17562848211002023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 02/04/2023] Open
Abstract
Patients with cholangiocarcinoma have poor survival since the majority of patients are diagnosed at a stage precluding surgical resection, due to locally irresectable tumors and/or metastases. Optimization of diagnostic strategies, with a principal role for tissue diagnosis, is essential to detect cancers at an earlier stage amenable to curative treatment. Current barriers for a tissue diagnosis include both insufficient tissue sampling and a difficult cyto- or histopathological assessment. During endoscopic retrograde cholangiopancreatography, optimal brush sampling includes obtaining more than one brush within an individual patient to increase its diagnostic value. Currently, no significant increase of the diagnostic accuracy for the new cytology brush devices aiming to enhance the cellularity of brushings versus standard biliary brush devices has been demonstrated. Peroral cholangioscopy with bile duct biopsies appears to be a valuable tool in the diagnostic work-up of indeterminate biliary strictures, and may overcome current technical difficulties of fluoroscopic-guided biopsies. Over the past years, molecular techniques to detect chromosomal instability, mutations and methylation profiling of tumors have revolutionized, and implementation of these techniques on biliary tissue during diagnostic work-up of biliary strictures may be awaited in the near future. Fluorescence in situ hybridization has already been implemented in routine diagnostic evaluation of biliary strictures in several centers. Next-generation sequencing is promising for standard diagnostic care in biliary strictures, and recent studies have shown adequate detection of prevalent genomic alterations in KRAS, TP53, CDKN2A, SMAD4, PIK3CA, and GNAS on biliary brush material. Detection of DNA methylation of tumor suppressor genes and microRNAs may evolve over the coming years to a valuable diagnostic tool for cholangiocarcinoma. This review summarizes optimal strategies for biliary tissue sampling during endoscopic retrograde cholangiopancreatography and focuses on the evolving molecular techniques on biliary tissue to improve the differentiation of benign and malignant biliary strictures.
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Affiliation(s)
- Eline J. C. A. Kamp
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Winand N. M. Dinjens
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Marco J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Pieter Jan F. de Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Annemarie C. de Vries
- Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, Room Na-609, Rotterdam, 3015 GD, The Netherlands
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Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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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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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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Perego G, Burgio V, Nozza R, Longobardo G, Bernecich M, Luciani A, Petrelli F. Is there any place for novel agents in treating biliary tract cancer? Med Oncol 2021; 38:19. [PMID: 33543377 DOI: 10.1007/s12032-021-01463-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/09/2021] [Indexed: 10/22/2022]
Abstract
Biliary tract cancer is an uncommon cancer in developed countries. In localized stages, surgery is the cornerstone of treatment with curative purpose. Conversely in advanced stages, chemotherapy with platinum-gemcitabine combination is the standard of care. Biliary tract cancers are a biologically heterogeneous group of malignancies, which perhaps explains the failure of targeted therapies in unselected patient populations to demonstrate benefit in advanced disease, although there are promises in selected populations (e.g. PD1/PD-L1 positive, BRAFV600E-mutated or IDH1-mutant). In view of the limited benefit of second line therapies in metastatic biliary tract cancer, various targeted agents have been tested in progressive disease. Furthermore, several ongoing trials are using next-generation sequencing of multiple genes to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially be used in pretreated disease (e.g. FGFR or IDH genes). Immunotherapy with immune checkpoint inhibitors may be interesting for patients whose tumors have programmed cell death 1 ligand 1 (PD-L1) overexpression. Ongoing and future trials will further advance our knowledge toward the optimal treatment strategy for the management of biliary tract cancer in its different stages, starting from metastatic and then reaching early stages of disease. We here provided an overview of these novel treatment strategies for advanced biliary tract cancers not amenable of curative treatment modalities.
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Affiliation(s)
| | | | - Renata Nozza
- School of Hospital Pharmacy, University of Milan, Milan, Italy
| | | | - Marco Bernecich
- School of Hospital Pharmacy, University of Milan, Milan, Italy
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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: 81] [Impact Index Per Article: 20.3] [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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Chiang NJ, Chen LT, Shan YS, Yeh CN, Chen MH. Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials. Biomolecules 2021; 11:97. [PMID: 33451059 PMCID: PMC7828560 DOI: 10.3390/biom11010097] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/15/2020] [Accepted: 01/10/2021] [Indexed: 12/11/2022] Open
Abstract
Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.
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Affiliation(s)
- Nai-Jung Chiang
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; (N.-J.C.); (L.-T.C.)
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan; (N.-J.C.); (L.-T.C.)
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan;
- Department of Surgery, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Chun-Nan Yeh
- Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Chang Gung University, Taoyuan 333, Taiwan
| | - Ming-Huang Chen
- Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan
- School of Medicine, National Yang Ming University, Taipei 112, Taiwan
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Sahin IH, Tan E, Kim R. Regorafenib, an investigational agent for the treatment of cholangiocarcinoma. Expert Opin Investig Drugs 2020; 30:333-341. [PMID: 33378249 DOI: 10.1080/13543784.2021.1867537] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Cholangiocarcinoma is a prevalent gastrointestinal cancer with a high mortality rate. A limited number of cholangiocarcinoma patients are diagnosed with early-stage disease but unfortunately, most patients present with an advanced-stage disease which is not amenable to curative surgical resection. AREAS COVERED We discuss regorafenib, a multi-kinase inhibitor, which has been investigated as a therapeutic agent in advanced stage biliary tract cancer patients in phase II trials. We examined the efficacy and toxicity of this agent and its potential in this patient population in the future. We also provide further insights on novel approaches to optimize the efficacy of regorafenib in cholangiocarcinoma patients. EXPERT OPINION The recent phase II trials of single-agent regorafenib in advanced stage biliary tumors revealed a modest activity in non enriched patient population and is currently part of the national comprehensive cancer network (NCCN) guidelines (Level 2B) in the refractory setting. However, more opportunities for this agent exist in combination approaches with other therapeutics such as immune checkpoint inhibitors. It is also important to recognize that the paradigm has significantly shifted for targeted therapy to more specific and more potent tyrosine kinase inhibitors targeting specific actionable genes.
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Affiliation(s)
- Ibrahim Halil Sahin
- Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, USA
| | - Elaine Tan
- Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, USA
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Okano N, Furuse J, Ueno M, Morizane C, Yamanaka T, Ojima H, Ozaka M, Sasaki M, Takahara N, Nakai Y, Kobayashi S, Morimoto M, Hosoi H, Maeno S, Nagashima F, Ikeda M, Okusaka T. Multicenter Phase II Trial of Axitinib Monotherapy for Gemcitabine-Based Chemotherapy Refractory Advanced Biliary Tract Cancer (AX-BC Study). Oncologist 2020; 26:97-e201. [PMID: 33010112 DOI: 10.1002/onco.13547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022] Open
Abstract
LESSONS LEARNED Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti-vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer. BACKGROUND There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC. METHODS Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients. RESULTS Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1-4.1). The median overall survival was 5.8 months (95% CI: 3.3-9.7). The response rate was 5.3% (95% CI: 0.0-15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS. CONCLUSION Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.
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Affiliation(s)
- Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Masato Ozaka
- Department of Hepatobiliary and Pancreatic Oncology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Mitsuhito Sasaki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | - Yousuke Nakai
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.,Department of Endoscopy and Endoscopic Surgery, The University of Tokyo, Tokyo, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, Japan
| | - Manabu Morimoto
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroko Hosoi
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoko Maeno
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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Xie C, McGrath NA, Monge Bonilla C, Fu J. Systemic treatment options for advanced biliary tract carcinoma. J Gastroenterol 2020; 55:944-957. [PMID: 32748173 PMCID: PMC7519922 DOI: 10.1007/s00535-020-01712-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/25/2020] [Indexed: 02/04/2023]
Abstract
Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.
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Affiliation(s)
- Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 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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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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Chakrabarti S, Kamgar M, Mahipal A. Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm. Cancers (Basel) 2020; 12:2039. [PMID: 32722188 PMCID: PMC7465131 DOI: 10.3390/cancers12082039] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/18/2022] Open
Abstract
Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.
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Affiliation(s)
- Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Mandana Kamgar
- Department of Hematology-Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (S.C.); (M.K.)
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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Athauda A, Fong C, Lau DK, Javle M, Abou-Alfa GK, Morizane C, Steward K, Chau I. Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation. Cancer Treat Rev 2020; 86:101998. [PMID: 32203843 PMCID: PMC8222858 DOI: 10.1016/j.ctrv.2020.101998] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 02/06/2023]
Abstract
Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.
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Affiliation(s)
- Avani Athauda
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Caroline Fong
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - David K Lau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
| | - Milind Javle
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Weill Medical College at Cornell University, New York, NY, USA.
| | - Chigusa Morizane
- National Cancer Center Hospital, Tsukiji, Tokyo 104-0045, Japan.
| | - Keith Steward
- QED Therapeutics Inc, 75 Federal Street, San Francisco, CA 94107, USA.
| | - Ian Chau
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.
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Demols A, Borbath I, Van den Eynde M, Houbiers G, Peeters M, Marechal R, Delaunoit T, Goemine JC, Laurent S, Holbrechts S, Paesmans M, Van Laethem JL. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann Oncol 2020; 31:1169-1177. [PMID: 32464280 DOI: 10.1016/j.annonc.2020.05.018] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).
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Affiliation(s)
- A Demols
- GE and Digestive Oncology Department, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
| | - I Borbath
- GE Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - M Van den Eynde
- GE Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - G Houbiers
- Oncology Department, Saint-Joseph Community Health Center, Liège, Belgium
| | - M Peeters
- Oncology Department - University Hospital Antwerp, Edegem, Belgium
| | - R Marechal
- GE and Digestive Oncology Department, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - T Delaunoit
- GE Department, INDC Entité Jolimontoise, Haine-St-Paul, Belgium
| | - J-C Goemine
- Oncology Department, Cliniques et Maternité Ste Elisabeth, Namur, Belgium
| | - S Laurent
- GE Department - Ghent University Hospital, Ghent, Belgium
| | - S Holbrechts
- Oncology Department, Centre Hospitalier Universitaire A. Paré, Mons, Belgium
| | - M Paesmans
- Data Center, Institut J. Bordet, Brussels, Belgium
| | - J-L Van Laethem
- GE and Digestive Oncology Department, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
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D'Andrea MR, Gill CM, Umphlett M, Tsankova NM, Fowkes M, Bederson JB, Brastianos PK, Shrivastava RK. Brain Metastases from Biliary Tract Cancers: A Case Series and Review of the Literature in the Genomic Era. Oncologist 2020; 25:447-453. [PMID: 31694894 PMCID: PMC7216433 DOI: 10.1634/theoncologist.2019-0306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/12/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC. MATERIALS AND METHODS We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed. RESULTS We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1-16.9). CONCLUSION Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes. IMPLICATIONS FOR PRACTICE In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.
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Affiliation(s)
- Megan R. D'Andrea
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Corey M. Gill
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Melissa Umphlett
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | | | - Mary Fowkes
- Department of Pathology, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Joshua B. Bederson
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
| | - Priscilla K. Brastianos
- Department of Neurology and Cancer Center, Massachusetts General HospitalBostonMassachusettsUSA
| | - Raj K. Shrivastava
- Department of Neurosurgery, Mount Sinai Medical CenterNew YorkNew YorkUSA
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Palmieri LJ, Lavolé J, Dermine S, Brezault C, Dhooge M, Barré A, Chaussade S, Coriat R. The choice for the optimal therapy in advanced biliary tract cancers: Chemotherapy, targeted therapies or immunotherapy. Pharmacol Ther 2020; 210:107517. [PMID: 32109491 DOI: 10.1016/j.pharmthera.2020.107517] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 02/18/2020] [Indexed: 01/09/2023]
Abstract
Biliary tract cancers (BTCs) represent a heterogeneous group that includes intrahepatic cholangiocarcinomas (CCAs), perihilar-CCAs or Klatskin tumors, extrahepatic-CCAs, and gallbladder adenocarcinoma. These entities have distinct demographics, risk factors, clinical presentation, and molecular characteristics. In advanced BTCs, the recommendations are mainly supporting a doublet chemotherapy regimen using cisplatin/gemcitabine (CisGem) with a 5-year overall survival rate close to 5% and median overall survival (mOS) of less than a year. The lack of overall efficacy stresses the need for personalized therapies. Recently, whole-genome and transcriptome sequencing highlighted the diversity of BTCs' subtypes. Distinct genetic alterations were retrieved according to the localization, with a high rate of potentially actionable alterations. Targeted therapies and immunotherapy have since then been tested for BTCs, trying to propose a more personalized treatment. This review describes the different therapeutic options, validated and in development, for patients with advanced BTCs.
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Affiliation(s)
- L-J Palmieri
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France.
| | - J Lavolé
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - S Dermine
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - C Brezault
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - M Dhooge
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France
| | - A Barré
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - S Chaussade
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
| | - R Coriat
- Gastroenterology and Digestive Oncology Department, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75014, France; Unité INSERM U1016, University of Paris, France
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Iyer P, Chen MH, Goyal L, Denlinger CS. Targets for therapy in biliary tract cancers: the new horizon of personalized medicine. Chin Clin Oncol 2020; 9:7. [PMID: 32146818 PMCID: PMC8650725 DOI: 10.21037/cco.2019.12.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022]
Abstract
Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.
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Affiliation(s)
- Pritish Iyer
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA
| | - Ming-Huang Chen
- Department of Oncology, Taipei Veteran's General Hospital, Taipei
| | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Crystal S Denlinger
- Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
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Xue L, Guo C, Zhang K, Jiang H, Pang F, Dou Y, Liu X, Lin H, Dong X, Zhao S, Yao M, Wang K, Feng Y, Gu W. Comprehensive molecular profiling of extrahepatic cholangiocarcinoma in Chinese population and potential targets for clinical practice. Hepatobiliary Surg Nutr 2019; 8:615-622. [PMID: 31929988 DOI: 10.21037/hbsn.2019.08.05] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Cholangiocarcinoma (CCA) is a diverse group of malignancies arising from the intra- or extrahepatic biliary epithelium and characterized by its late diagnosis and fatal outcome. Extrahepatic cholangiocarcinoma (ECC) accounts for 90% of CCA. However, little is known about the comprehensive genomic alterations of ECC in Chinese population for providing clinical managements especially targeted therapy. Methods Comprehensive genomic profiling (CGP) was performed with next generation sequencing panel on paraffin-embedded tumor from a cohort of 80 Chinese ECC patients. Results The most frequently altered genes were TP53 (68%), KRAS (46%), SMAD4 (22%), ARID1A (20%) and CDKN2A (19%). Mutual exclusivity was observed between multiple genes including ARID1A:TP53, KRAS:LRP1B and NF2:TP53. Genetic alterations with potential therapeutic implications were identified in 43% of patients. The top three actionable alterations include CDKN2A (n=11), BRAF (n=5) and ERBB2 (n=4). Potentially actionable alterations were mainly enriched in the G1-S transition, homologous recombination repair, MAPK/ERK pathway. Conclusions This is the largest data set of ECC cases providing a comprehensive view on genetic alterations in Chinese population which differs significantly from a US cohort, and indicates the potential clinical implications for targeted therapies.
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Affiliation(s)
- Liang Xue
- Department of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chao Guo
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China
| | - Kang Zhang
- Department of Cancer, People's Hospital of Wuzhou, Wuzhou 543000, China
| | - Hang Jiang
- Department of Hepato-Biliary-Pancreatic Surgery, The Third People's Hospital of Yunnan Province, Kunming 650011, China
| | - Fei Pang
- OrigiMed Inc., Shanghai 201114, China
| | - Ying Dou
- OrigiMed Inc., Shanghai 201114, China
| | | | | | | | | | - Ming Yao
- OrigiMed Inc., Shanghai 201114, China
| | - Kai Wang
- OrigiMed Inc., Shanghai 201114, China
| | - Yujie Feng
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Weiguang Gu
- Department of Medical Oncology, People's Hospital of Nanhai District, Foshan 528200, China.,Department of Medical Oncology, Southern Medical University Nanfang Hospital, Guangzhou 510515, China
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Kim Y, Bang SS, Jee S, Park S, Shin SJ, Jang K. Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma. Cancer Res Treat 2019; 52:481-491. [PMID: 31645095 PMCID: PMC7176974 DOI: 10.4143/crt.2019.370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/23/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Mesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimeric transmembrane receptor tyrosine kinase for the hepatocyte growth factor. Aberrant MET signaling has been described in several solid tumors-especially non-small cell lung cancer- and is associated with tumor progression and adverse prognosis. As MET is a potential therapeutic target, information regarding its prevalence and clinicopathological relevance is crucial. MATERIALS AND METHODS We investigated MET expression and gene amplification in 113 gallbladder cancers using tissue microarray. Immunohistochemistry was used to evaluate MET overexpression, and silver/fluorescence in situ hybridization (ISH) was used to assess gene copy number. RESULTS MET overexpression was found in 37 cases of gallbladder carcinoma (39.8%), and gene amplification was present in 17 cases (18.3%). MET protein expression did not correlate with MET amplification. MET amplification was significantly associated with aggressive clinicopathological features, including high histological grade, advanced pT category, lymph node metastasis, and advanced American Joint Committee on Cancer stage. There was no significant correlation between any clinicopathological factors and MET overexpression. No difference in survival was found with respect to MET overexpression and amplification status. CONCLUSION Our data suggested that MET might be a potential therapeutic target for targeted therapy in gallbladder cancer, because MET amplification was found in a subset of tumors associated with adverse prognostic factors. Detection of MET amplification by ISH might be a useful predictive biomarker test for anti-MET therapy.
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Affiliation(s)
- Yeseul Kim
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seong Sik Bang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seungyun Jee
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Sungeon Park
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Su-Jin Shin
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
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