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Cappuyns S, Piqué-Gili M, Esteban-Fabró R, Philips G, Balaseviciute U, Pinyol R, Gris-Oliver A, Vandecaveye V, Abril-Fornaguera J, Montironi C, Bassaganyas L, Peix J, Zeitlhoefler M, Mesropian A, Huguet-Pradell J, Haber PK, Figueiredo I, Ioannou G, Gonzalez-Kozlova E, D'Alessio A, Mohr R, Meyer T, Lachenmayer A, Marquardt JU, Reeves HL, Edeline J, Finkelmeier F, Trojan J, Galle PR, Foerster F, Mínguez B, Montal R, Gnjatic S, Pinato DJ, Heikenwalder M, Verslype C, Van Cutsem E, Lambrechts D, Villanueva A, Dekervel J, Llovet JM. Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma. J Hepatol 2025; 82:1036-1049. [PMID: 39709141 PMCID: PMC12086051 DOI: 10.1016/j.jhep.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 11/29/2024] [Accepted: 12/07/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND & AIMS The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo+bev. METHODS We harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of patients with advanced HCC treated with atezo+bev (n = 317) vs. atezolizumab (n = 47) or sorafenib (n = 58) as comparators. RESULTS We unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterised by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune-rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs. sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define "Immune-competent" and "Angiogenesis-driven" molecular subgroups, each associated with a significantly longer OS with atezo+bev vs. sorafenib (p of interaction = 0.027), and a "Resistant" subset. CONCLUSION Our study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC ("Immune-competent" and "Angiogenesis-driven") as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance. IMPACT AND IMPLICATIONS Atezolizumab + bevacizumab (atezo+bev) is standard of care in advanced hepatocellular carcinoma (HCC), yet molecular determinants of clinical benefit to the combination remain unclear. This study harnesses the power of single-cell RNA sequencing, deriving gene expression signatures representing 21 cell subtypes in the advanced HCC microenvironment. By applying these signatures to RNA-sequencing samples, we reveal two distinct response patterns to atezo+bev and define molecular subgroups of patients ("Immune-competent" and "Angiogenesis-driven" vs. "Resistant") with differential clinical outcomes upon treatment with atezo+bev, pointing towards the role of immunosuppressive myeloid cell types and Notch pathway activation in primary resistance to atezo+bev. These results may help refine treatment strategies and improve outcomes for patients with advanced HCC, while also guiding future research aimed at overcoming resistance mechanisms.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/mortality
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/mortality
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Bevacizumab/administration & dosage
- Bevacizumab/therapeutic use
- Male
- Female
- Single-Cell Analysis/methods
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Sequence Analysis, RNA/methods
- Middle Aged
- Tumor Microenvironment
- Drug Resistance, Neoplasm/genetics
- Sorafenib
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Affiliation(s)
- Sarah Cappuyns
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Centre for Cancer Biology, Leuven, Belgium; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marta Piqué-Gili
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Roger Esteban-Fabró
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Gino Philips
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Centre for Cancer Biology, Leuven, Belgium
| | - Ugne Balaseviciute
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Albert Gris-Oliver
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Vincent Vandecaveye
- Radiology Department, University Hospitals Leuven, Leuven, Belgium; Laboratory of Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Jordi Abril-Fornaguera
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Carla Montironi
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Pathology Department and Molecular Biology Core, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Laia Bassaganyas
- Institut de Génomique Fonctionnelle, Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | - Judit Peix
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Marcus Zeitlhoefler
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Agavni Mesropian
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Júlia Huguet-Pradell
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain
| | - Philipp K Haber
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Igor Figueiredo
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giorgio Ioannou
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Edgar Gonzalez-Kozlova
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, UK
| | - Anja Lachenmayer
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jens U Marquardt
- Department of Medicine I, University Medical Center Schleswig Holstein Campus Lübeck, Lübeck, Germany
| | - Helen L Reeves
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK; Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer, Medical School, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Fabian Finkelmeier
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Jörg Trojan
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Peter R Galle
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
| | - Friedrich Foerster
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
| | - Beatriz Mínguez
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Liver Diseases Research Group, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; CIBERehd, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Robert Montal
- Department of Medical Oncology, Cancer Biomarkers Research Group, Hospital Universitari Arnau de Vilanova, IRBLleida, University of Lleida (UdL), Catalonia, Spain
| | - Sacha Gnjatic
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK; Department of Translational Medicine, Università Del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Chris Verslype
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Eric Van Cutsem
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Centre for Cancer Biology, Leuven, Belgium
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Jeroen Dekervel
- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, 08010, Spain.
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Su J, Wang J, Chen W, Xu Y, Yang W, Liu W, Wang Z, Huang M. Unveiling MAGEA3: a novel predictive biomarker for bevacizumab resistance in colorectal cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:22. [PMID: 40342736 PMCID: PMC12059477 DOI: 10.20517/cdr.2025.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025]
Abstract
Aim: Bevacizumab has long been a cornerstone in the treatment of colorectal cancer (CRC), serving as a fundamental antiangiogenic therapeutic option. However, a significant proportion of patients exhibit insensitivity to bevacizumab, and no reliable biomarker has been established to predict treatment efficacy. Notably, while many angiogenic factors in tumors have been extensively studied, they have failed to consistently demonstrate reliable predictive value for patient survival outcomes in CRC. This study is designed to screen tumor biomarkers with predictive value for bevacizumab resistance in CRC. Methods: Online CRC databases with bevacizumab treatment were downloaded from the GEO datasets along with the TCGA database, which were then analyzed to generate genes overexpressed in bevacizumab non-responders. In vitro experiments using colorectal cancer cell lines were then performed to explore the underlying mechanism of the candidate gene that impacts bevacizumab efficacy. Finally, clinical samples of CRC were collected to validate the predictive effect of the candidate gene on bevacizumab efficacy. Results: We conducted comprehensive analyses of CRC patient datasets, identifying MAGEA3 as a pivotal gene that is not only highly upregulated in bevacizumab-resistant primary CRC but also strongly associated with poor overall survival prognosis. Our in vitro experiments revealed a novel mechanistic insight: MAGEA3 specifically inhibits the expression and secretion of VEGF through the mTOR signaling pathway in colorectal cancer cells, while exhibiting minimal impact on other key angiogenic factors such as PDGF, FGF, and ANGPT2. This selective regulation of VEGF provides a molecular basis for MAGEA3's role in bevacizumab resistance. Furthermore, we discovered that MAGEA3 significantly impairs mitochondrial function in cancer cells, suggesting an additional layer of complexity in its oncogenic role. Clinically, our findings demonstrated that high baseline levels of MAGEA3 in CRC patients were strongly associated with worse progression-free survival (PFS) following bevacizumab treatment. Conclusion: Collectively, these findings position MAGEA3 as a promising predictive biomarker for bevacizumab resistance in CRC, offering a potential solution to the longstanding challenge of treatment stratification.
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Affiliation(s)
- Juncheng Su
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jiahui Wang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weilin Chen
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yingjie Xu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wen Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiwei Liu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Masha Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Gila F, Khoddam S, Jamali Z, Ghasemian M, Shakeri S, Dehghan Z, Fallahi J. Personalized medicine in colorectal cancer: a comprehensive study of precision diagnosis and treatment. Per Med 2025; 22:59-81. [PMID: 39924822 DOI: 10.1080/17410541.2025.2459050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
Colorectal cancer is a common and fatal disease that affects many people globally. CRC is classified as the third most prevalent cancer among males and the second most frequent cancer among females worldwide. The purpose of this article is to examine how personalized medicine might be used to treat colorectal cancer. The classification of colorectal cancer based on molecular profiling, including the detection of significant gene mutations, genomic instability, and gene dysregulation, is the main topic of this discussion. Advanced technologies and biomarkers are among the detection methods that are explored, demonstrating their potential for early diagnosis and precise prognosis. In addition, the essay explores the world of treatment possibilities by providing light on FDA-approved personalized medicine solutions that provide individualized and precise interventions based on patient characteristics. This article assesses targeted treatments like cetuximab and nivolumab, looks at the therapeutic usefulness of biomarkers like microsatellite instability (MSI) and circulating tumor DNA (ctDNA), and investigates new approaches to combat resistance. Through this, our review provides a thorough overview of personalized medicine in the context of colorectal cancer, ultimately highlighting its potential to revolutionize the field and improve patient care.
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Affiliation(s)
- Fatemeh Gila
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Khoddam
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Jamali
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohmmad Ghasemian
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shayan Shakeri
- Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Dehghan
- Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhang J, Deng YT, Liu J, Gan L, Jiang Y. Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer. Cancer Biol Ther 2024; 25:2366451. [PMID: 38857055 PMCID: PMC11168221 DOI: 10.1080/15384047.2024.2366451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/06/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.
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Affiliation(s)
- Jie Zhang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yao-Tiao Deng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Jie Liu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - Lu Gan
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yu Jiang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
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Okawa M, Yamakuchi M, Bibek A, Takenouchi K, Maywar DN, Yamada S, Inoue K, Higurashi K, Nakazawa J, Kawahira M, Kodama T, Tanoue K, Oyama Y, Higashi S, Fujisaki C, Hashinokuchi H, Tabaru A, Kanda H, Tachioka S, Imoto Y, Hashiguchi T, Soga Y. Plasma and serum concentrations of VEGF-A121, but not of VEGF-A165, increase post-bevacizumab administration. PLoS One 2024; 19:e0316035. [PMID: 39700124 DOI: 10.1371/journal.pone.0316035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment. METHODS An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy. RESULTS The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood. CONCLUSIONS The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care.
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Affiliation(s)
- Masashi Okawa
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Munekazu Yamakuchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Aryal Bibek
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazunori Takenouchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Drew N Maywar
- Electrical and Computer Engineering Technology, Rochester Institute of Technology, Rochester, New York, United States of America
| | | | | | | | - Junichi Nakazawa
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Masahiro Kawahira
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Tomoko Kodama
- Department of Medical Oncology, Kagoshima City Hospital, Kagoshima, Japan
| | - Kiyonori Tanoue
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Yoko Oyama
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Sadayuki Higashi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Chieko Fujisaki
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | | | - Akito Tabaru
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideaki Kanda
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shuji Tachioka
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yutaka Imoto
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Teruto Hashiguchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Kagoshima University Hospital Clinical Laboratory, Kagoshima, Japan
| | - Yoshiharu Soga
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Keller S, Kunz U, Schmid U, Beusmans J, Büchert M, He M, Jayadeva G, Le Tourneau C, Luedtke D, Niessen HG, Oum'hamed Z, Pleiner S, Wang X, Graeser R. Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor. J Transl Med 2024; 22:934. [PMID: 39402675 PMCID: PMC11476076 DOI: 10.1186/s12967-024-05612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 08/18/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. METHODS Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. RESULTS DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. CONCLUSIONS The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. TRIAL REGISTRATION NCT02674152 and NCT02689505.
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Affiliation(s)
- Sascha Keller
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Ulrich Kunz
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Ulrike Schmid
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Martin Büchert
- Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Min He
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Girish Jayadeva
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Christophe Le Tourneau
- Department of Drug Development and Innovation (D3i), Institut Curie, INSERM U900 Research Unit, Paris-Saclay University, Saint-Cloud, Paris, France
| | - Doreen Luedtke
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Heiko G Niessen
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Zohra Oum'hamed
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Sina Pleiner
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Ralph Graeser
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
- Pieris Pharmaceuticals GmbH, Zeppelinstrasse 3, 85399, Hallbergmoos, Germany.
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7
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González A, Badiola I, Fullaondo A, Rodríguez J, Odriozola A. Personalised medicine based on host genetics and microbiota applied to colorectal cancer. ADVANCES IN GENETICS 2024; 112:411-485. [PMID: 39396842 DOI: 10.1016/bs.adgen.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) ranks second in incidence and third in cancer mortality worldwide. This situation, together with the understanding of the heterogeneity of the disease, has highlighted the need to develop a more individualised approach to its prevention, diagnosis and treatment through personalised medicine. This approach aims to stratify patients according to risk, predict disease progression and determine the most appropriate treatment. It is essential to identify patients who may respond adequately to treatment and those who may be resistant to treatment to avoid unnecessary therapies and minimise adverse side effects. Current research is focused on identifying biomarkers such as specific mutated genes, the type of mutations and molecular profiles critical for the individualisation of CRC diagnosis, prognosis and treatment guidance. In addition, the study of the intestinal microbiota as biomarkers is being incorporated due to the growing scientific evidence supporting its influence on this disease. This article comprehensively addresses the use of current and emerging diagnostic, prognostic and predictive biomarkers in precision medicine against CRC. The effects of host genetics and gut microbiota composition on new approaches to treating this disease are discussed. How the gut microbiota could mitigate the side effects of treatment is reviewed. In addition, strategies to modulate the gut microbiota, such as dietary interventions, antibiotics, and transplantation of faecal microbiota and phages, are discussed to improve CRC prevention and treatment. These findings provide a solid foundation for future research and improving the care of CRC patients.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Iker Badiola
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | | | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
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8
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Zhao C, Zeng Y, Kang N, Liu Y. A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies. Drug Dev Res 2024; 85:e22257. [PMID: 39245913 DOI: 10.1002/ddr.22257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 07/20/2024] [Accepted: 08/26/2024] [Indexed: 09/10/2024]
Abstract
Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to "starve" the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.
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Affiliation(s)
- Chen Zhao
- Department of Pharmacy, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Yuan Zeng
- Department of Clinical Pharmacology and Bioanalytics, Pfizer (China) Research and Development Co., Ltd., Shanghai, People's Republic of China
| | - Nannan Kang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yu Liu
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, People's Republic of China
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Ceci C, Ruffini F, Falconi M, Atzori MG, Falzon A, Lozzi F, Iacovelli F, D'Atri S, Graziani G, Lacal PM. Pharmacological inhibition of PDGF-C/neuropilin-1 interaction: A novel strategy to reduce melanoma metastatic potential. Biomed Pharmacother 2024; 176:116766. [PMID: 38788599 DOI: 10.1016/j.biopha.2024.116766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/30/2024] [Accepted: 05/17/2024] [Indexed: 05/26/2024] Open
Abstract
Activation of neuropilin-1 (NRP-1) by platelet derived growth factor (PDGF)-C sustains melanoma invasiveness. Therefore, in the search of novel agents capable of reducing melanoma spreading, PDGF-C/NRP-1 interaction was investigated as a potential druggable target. Since the PDGF-C region involved in NRP-1 binding is not yet known, based on the sequence and structural homology between PDGF-C and vascular endothelial growth factor-A (VEGF-A), we hypothesized that the NRP-1 b1 domain region involved in the interaction with VEGF-A might also be required for PDGF-C binding. Hence, this region was selected from the protein crystal structure and used as target in the molecular docking procedure. In the following virtual screening, compounds from a DrugBank database were used as query ligands to identify agents potentially capable of disrupting NRP-1/PDGF-C interaction. Among the top 45 candidates with the highest affinity, five drugs were selected based on the safety profile, lack of hormonal effects, and current availability in the market: the antipsychotic pimozide, antidiabetic gliclazide, antiallergic cromolyn sodium, anticancer tyrosine kinase inhibitor entrectinib, and antihistamine azelastine. Analysis of drug influence on PDGF-C in vitro binding to NRP-1 and PDGF-C induced migration of human melanoma cells expressing NRP-1, indicated gliclazide and entrectinib as the most specific agents that were active at clinically achievable and non-toxic concentrations. Both drugs also reverted PDGF-C ability to stimulate extracellular matrix invasion by melanoma cells resistant to BRAF inhibitors. The inhibitory effect on tumor cell motility involved a decrease of p130Cas phosphorylation, a signal transduction pathway activated by PDGF-C-mediated stimulation of NRP-1.
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Affiliation(s)
- Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Mattia Falconi
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Andrea Falzon
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Flavia Lozzi
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | | | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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Mazard T, Mollevi C, Loyer EM, Léger J, Chautard R, Bouché O, Borg C, Armand-Dujardin P, Bleuzen A, Assenat E, Lecomte T. Prognostic value of the tumor-to-liver density ratio in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. A post-hoc study of the STIC-AVASTIN trial. Cancer Imaging 2024; 24:77. [PMID: 38886836 PMCID: PMC11181627 DOI: 10.1186/s40644-024-00722-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 06/10/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND The Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based chemotherapy. In a first cohort of patients with colorectal cancer liver metastases (CRLM), we showed that variations of the tumor-to-liver density (TTLD) ratio and modified size-based criteria determined using computed tomography (CT) data at the first restaging were better prognostic criteria than the RECIST. The aims of this study were to confirm the relevance of these radiological biomarkers as early predictors of the long-term clinical outcome and to assess their correlation with contrast-enhanced ultrasound (CEUS) parameters in a new patient cohort. METHODS In this post-hoc study of the multicenter STIC-AVASTIN trial, we retrospectively reviewed CT data of patients with CRLM treated with bevacizumab-based regimens. We determined the size, density and TTLD ratio of target liver lesions at baseline and at the first restaging and also performed a morphologic evaluation according to the MD Anderson criteria. We assessed the correlation of these parameters with progression-free survival (PFS) and overall survival (OS) using the log-rank test and a Cox proportional hazard model. We also examined the association between TTLD ratio and quantitative CEUS parameters. RESULTS This analysis concerned 79 of the 137 patients included in the STIC-AVASTIN trial. PFS and OS were significantly longer in patients with tumor size reduction > 15% at first restaging, but were not correlated with TTLD ratio variations. However, PFS was longer in patients with TTLD ratio > 0.6 at baseline and first restaging than in those who did not reach this threshold. In the multivariate analysis, only baseline TTLD ratio > 0.6 was a significant survival predictor. TTLD ratio > 0.6 was associated with improved perfusion parameters. CONCLUSIONS Although TTLD ratio variations did not correlate with the long-term clinical outcomes, TTLD absolute values remained a good predictor of survival at baseline and first restaging, and may reflect tumor microvascular features that might influence bevacizumab-based treatment efficiency. TRIAL REGISTRATION NCT00489697, registration number of the STIC-AVASTIN trial.
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Affiliation(s)
- Thibault Mazard
- Medical Oncology Department, Montpellier Cancer Institute (ICM), University of Montpellier, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, 208 avenue des apothicaires, Parc Euromédecine, Montpellier Cedex 5, Montpellier, 34298, France.
| | - Caroline Mollevi
- Institute Desbrest of Epidemiology and Public Health, University of Montpellier, INSERM, Cancer Institute of Montpellier, Montpellier, France
| | - Evelyne M Loyer
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Julie Léger
- INSERM CIC 1415, CHRU de Tours, Tours Cedex 9, 37044, France
| | - Romain Chautard
- Department of Hepatogastroenterology and Digestive Oncology, UMR INSERM U 1069, Hôpital Trousseau, CHRU de Tours, Université de Tours, Tours Cedex 9, 37044, France
| | - Olivier Bouché
- Department of Hepatogastroenterology, Hôpital Robert Debré, CHU de Reims, Avenue Général Koenig, Reims Cedex, 51092, France
| | - Christophe Borg
- Department of Medical Oncology, Hôpital Jean Minjoz, CHRU de Besançon, 3 Boulevard Alexandre Fleming, Besançon, 25000, France
| | | | - Aurore Bleuzen
- Department of Radiology, CHRU de Tours, Tours Cedex 9, 37044, France
| | - Eric Assenat
- Medical Oncology Department, Montpellier Cancer Institute (ICM), University of Montpellier, CHU Montpellier, Montpellier, France
| | - Thierry Lecomte
- Department of Hepatogastroenterology and Digestive Oncology, UMR INSERM U 1069, Hôpital Trousseau, CHRU de Tours, Université de Tours, Tours Cedex 9, 37044, France
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11
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Venken T, Miller IS, Arijs I, Thomas V, Barat A, Betge J, Zhan T, Gaiser T, Ebert MP, O'Farrell AC, Prehn J, Klinger R, O'Connor DP, Moulton B, Murphy V, Serna G, Nuciforo PG, McDermott R, Bird B, Leonard G, Grogan L, Horgan A, Schulte N, Moehler M, Lambrechts D, Byrne AT. Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients. NPJ Genom Med 2024; 9:33. [PMID: 38811554 PMCID: PMC11137102 DOI: 10.1038/s41525-024-00415-x] [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: 09/22/2023] [Accepted: 05/02/2024] [Indexed: 05/31/2024] Open
Abstract
To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
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Affiliation(s)
- Tom Venken
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Ian S Miller
- Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ingrid Arijs
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Valentina Thomas
- Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ana Barat
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
- DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Timo Gaiser
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Alice C O'Farrell
- Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen Prehn
- Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Rut Klinger
- UCD Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Darran P O'Connor
- Department of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | - Garazi Serna
- Val d'Hebron Institute of Oncology, Barcelona, Spain
| | | | - Ray McDermott
- Cancer Trials Ireland, Dublin, Ireland
- Department of Medical Oncology, Tallaght University Hospital, Dublin, Ireland
- Department of Medical Oncology, St. Vincent's University Hospital, Dublin, Ireland
| | - Brian Bird
- Bon Secours Cork Cancer Centre, Bon Secours Hospital Cork, Cork, Ireland
| | | | - Liam Grogan
- Medical Oncology Department, Beaumont Hospital, Dublin, Ireland
| | - Anne Horgan
- Department of Medical Oncology, South East Cancer Center, University Hospital Waterford, Waterford, Ireland
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Markus Moehler
- Department of Medicine, Johannes-Gutenberg University Clinic, Mainz, Germany
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
- VIB Center for Cancer Biology, Leuven, Belgium.
| | - Annette T Byrne
- Precision Cancer Medicine Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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12
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Li S, Yang X, Lu T, Yuan L, Zhang Y, Zhao J, Deng J, Xue C, Sun Q, Liu X, Zhang W, Zhou J. Extracellular volume fraction can predict the treatment response and survival outcome of colorectal cancer liver metastases. Eur J Radiol 2024; 175:111444. [PMID: 38531223 DOI: 10.1016/j.ejrad.2024.111444] [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: 11/24/2023] [Revised: 03/09/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
OBJECTIVE To assess the prognostic value of pre- and post-therapeutic changes in extracellular volume (ECV) fraction of liver metastases (LMs) for treatment response (TR) and survival outcomes in colorectal cancer liver metastases (CRLM). METHODS 186 LMs were confirmed by pathology or follow-up (Training: 130; Test: 56). We analyzed the changes in ECV fraction of LMs before and after 2 cycles of chemotherapy combined with bevacizumab. After 12 cycles, we evaluated the TR on LMs based on the RECIST v1.1. Relative changes in ECV fraction and Hounsfield Units (HU), defined as ΔECV and ΔHU, were associated with progression-free survival (PFS), overall survival (OS), and TR. We identified TR predictors with multivariate logistic regression and PFS, OS risk factors with COX analysis. RESULTS 186 LMs were classified as TR lesions (TR+: 84) and non-TR lesions (TR-:102). ΔECV, ΔHUA-E, and texture could distinguish the TR of LMs in training and test set (P < 0.05). ΔECV [Odds ratio (OR): 1.03; 95% Confidence interval (CI): 1.02-1.05, P < 0.01] was an independent predictor of TR-. Area under the curve (AUC), sensitivity and specificity of TR model in training and test set were 0.87, 0.84, 90.14%, 90.32%, 72.88%, 64.00%, respectively. High CRD_score indicates that patients have shorter PFS [Hazard ratio (HR): 2.01; 95%CI: 1.02-3.98, P = 0.045)] and OS (HR: 1.89, 95%CI: 1.04-3.42, P = 0.038). CONCLUSION ΔECV can be used as an independent predictor of TR of CRLM chemotherapy combined with bevacizumab.
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Affiliation(s)
- Shenglin Li
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China.
| | - Xinmei Yang
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Ting Lu
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Long Yuan
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Yuting Zhang
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China
| | - Jun Zhao
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China
| | - Juan Deng
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Caiqiang Xue
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Qiu Sun
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China
| | - Xianwang Liu
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Wenjuan Zhang
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China
| | - Junlin Zhou
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No. 82, Chengguan District, Lanzhou 730030, China; Second Clinical School, Lanzhou University, Lanzhou, China; Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China; Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China.
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Petracci E, Passardi A, Biggeri A, Valgiusti M, Monti M, Frassineti GL, Nanni O, Scarpi E. Baseline and Longitudinal Neutrophil-to-Lymphocyte Ratio as Prognostic Factor for Metastatic Colorectal Cancer: A Secondary Analysis of the ITACa Randomized Trial. JCO Precis Oncol 2024; 8:e2300256. [PMID: 38295317 PMCID: PMC10843252 DOI: 10.1200/po.23.00256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/16/2023] [Accepted: 11/16/2023] [Indexed: 02/02/2024] Open
Abstract
PURPOSE We aimed to investigate the prognostic role of baseline and longitudinal levels of neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy + bevacizumab (CT + B) or chemotherapy only. Additionally, we investigated whether treatment outcomes were mediated by the longitudinal biomarker. METHODS Data from an Italian randomized phase III trial were used. The main end point was progression-free survival (PFS). To address research questions, a series of joint models of longitudinal and survival data were specified, and the direct and indirect treatment effects were quantified. RESULTS Data for 239 patients, 113 (47.3%) treated with CT + B and 126 (52.7%) with CT only, were included in the analyses. The effect of NLR seemed to be mediated by the longitudinal trajectory of the biomarker. Only in the patient subgroup treated with CT + B, the baseline NLR retained a direct effect on PFS. Regarding the effect of treatment on PFS, two scenarios were observed. In the subgroup of patients with low baseline, NLR bevacizumab showed a direct protective effect only (hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.98]), whereas in the subgroup with high baseline NLR, there was evidence for an adverse direct effect (HR, 1.63 [95% CI, 1.03 to 2.57]) and a protective indirect-which is mediated by the longitudinal biomarker-effect (HR, 0.71 [95% CI, 0.55 to 0.90]). CONCLUSION In our study, inflammatory indexes collected longitudinally showed a significant adverse prognostic role, thus suggesting the collection and use of such data for better clinical decision making. In the specific setting, we considered this is particularly important as the treatment effect seemed to be modified by both the baseline and longitudinal inflammation statuses. However, further research is needed to understand the possible factors underlying these results.
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Affiliation(s)
- Elisabetta Petracci
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Annibale Biggeri
- Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
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Passardi A, Azzali I, Bittoni A, Marisi G, Rebuzzi F, Molinari C, Bartolini G, Matteucci L, Sullo FG, Debonis SA, Gallio C, Monti M, Valgiusti M, Muratore M, Rapposelli IG, Ulivi P, Frassineti GL. Inflammatory indices as prognostic markers in metastatic colorectal cancer patients treated with chemotherapy plus Bevacizumab. Ther Adv Med Oncol 2023; 15:17588359231212184. [PMID: 38107830 PMCID: PMC10722949 DOI: 10.1177/17588359231212184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/19/2023] [Indexed: 12/19/2023] Open
Abstract
Background Validated predictors of sensitivity or resistance to Bevacizumab (Bev) are not available, and Inflammatory Indexes (IIs) has been reported to be useful prognostic factors in various malignant solid tumours, including metastatic colorectal cancer (mCRC). Objectives To explore the prognostic value of IIs in mCRC patients treated with first-line chemotherapy plus Bev. Design One hundred and eighty-two patients diagnosed with mCRC and treated with first line chemotherapy plus Bev were considered for this prospective non-pharmacological study. Neutrophil, lymphocyte, platelet, aspartate transaminase (AST) and lactate dehydrogenase (LDH) tests were carried out at baseline and before each treatment cycle, according to clinical practice. Methods Pre-treatment Systemic Immune-inflammation Index (SII), Colon Inflammatory Index (CII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) were evaluated to assess a correlation with progression-free survival (PFS) and overall survival (OS). Results In the overall population, PFS and OS were lower in patients with high SII (HR 1.64, p = 0.006 and HR 1.75, p = 0.004, respectively) and high ALRI (HR 2.13, p = 0.001 and HR 1.76, p = 0.02, respectively), but no difference was detected according to CII value. The multivariate analysis confirmed both SII and ALRI as independent prognostic factors for PFS (HR 1.64 and 2.82, respectively) and OS (HR 1.65 and 2.12, respectively). Conclusion Our results demonstrate and confirm that IIs, and in particular SII and ALRI, are easy to measure prognostic markers for patient candidates to first line chemotherapy plus Bev for mCRC.
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Affiliation(s)
- Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Irene Azzali
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Via P. Maroncelli 40, Meldola 47014, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Francesca Rebuzzi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Chiara Molinari
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Francesco Giulio Sullo
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Silvia Angela Debonis
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Chiara Gallio
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Manlio Monti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Margherita Muratore
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Paola Ulivi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
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Wang YB, Zheng KW, Hu YY, Salameen H, Zhu ZY, Wu FF, Ding X. VEGF/Nrp1/HIF-1α promotes proliferation of hepatocellular carcinoma through a positive feedback loop. Med Oncol 2023; 40:339. [PMID: 37875691 DOI: 10.1007/s12032-023-02202-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/19/2023] [Indexed: 10/26/2023]
Abstract
To investigate the role of neuropilin1 (Nrp1) in glucose metabolism and proliferation of hepatocellular carcinoma (HCC) cells and to analyze its mechanism of action. The CRISPR gene knockout technique was used to knock out the Nrp1 gene in two HCC cell lines. The effect of Nrp1 on the proliferation of HCC cells was assessed in the CCK8 assay and plate cloning assay. The expression levels of glucose consumption, lactate production, and essential proteins of the glycolytic pathway were detected to explore the effect of Nrp1 on glucose metabolism in HCC cells. Using CoCl2 to revert the expression of hypoxia inducible factor-1α (HIF-1α), the role of HIF-1α in the pro-HCC cell metabolism of Nrp1 were demonstrated. The protein synthesis inhibitor CHX and proteasome inhibitor MG-132 was used to analyze the molecular mechanism of action of Nrp1 on HIF-1α. The Kaplan-Meier method was used to calculate survival rates and plot survival curves. Based on the CCK8 assay and plate cloning assay, we found that Nrp1 knockout significantly inhibited the proliferation of HCC cells. Nrp1 inhibitor suppressed lactate production and glucose consumption in HCC cells. Knockout of Nrp1 decreased the expression of glycolytic pathway-related proteins and HIF-1α protein. Furthermore, by joint use of CoCl2 and NRP1 knockout, we confirmed that reverting HIF-1α expression could reverse the effect of Nrp1 knockout on HCC cell metabolism in vitro. Mechanistically, Nrp1 showed a close correlation with the stability of HIF-1α protein in protein stability assay. Finally, we revealed that high expression of Nrp1 in HCC tissues was associated with poor overall survival and disease-free survival of the patients. Nrp1 accelerates glycolysis and promotes proliferation of HCC by regulating HIF-1α protein stability and through the VEGF/Nrp1/HIF-1α positive feedback loop.
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Affiliation(s)
- Yun-Bing Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China
| | - Kai-Wen Zheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China
- Department of Hepatobiliary Surgery, The People's Hospital of Rongchang District, Chongqing, People's Republic of China
| | - Yi-Yu Hu
- The Second Clinical College, Chongqing Medical University, Chongqing, People's Republic of China
| | - Haitham Salameen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China
| | - Zhe-Yu Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China
| | - Fei-Fan Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China
| | - Xiong Ding
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, No. 288, Chayuan Tianwen Avenue, Nan'an District, Chongqing, People's Republic of China.
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Ilie MD, De Alcubierre D, Carretti AL, Jouanneau E, Raverot G. Therapeutic targeting of the pituitary tumor microenvironment. Pharmacol Ther 2023; 250:108506. [PMID: 37562699 DOI: 10.1016/j.pharmthera.2023.108506] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/28/2023] [Accepted: 08/07/2023] [Indexed: 08/12/2023]
Abstract
The tumor microenvironment (TME), the complex environment in which tumors develop, has been increasingly targeted for cancer treatment in recent years. Aggressive pituitary tumors and pituitary carcinomas have been so far targeted with immune-checkpoint inhibitors (28 cases, including a large cohort), and anti-angiogenic drugs (34 cases), specifically bevacizumab (30 cases), sunitinib (three cases), and apatinib (one case). Here, we reviewed all these cases, reporting tumor response, potential predictors of response, as well as adverse events. Given that the histological type could potentially influence treatment response, we present the existing data separately for each type. Briefly, under ICIs, complete response was noted in one case, partial response in a third of cases, stable disease in 10% of cases, while 54% of tumors progressed. Under BVZ monotherapy, most cases (57%) showed stable disease, while 36% of tumors progressed; partial response was reported in only one case. The three cases treated with sunitinib monotherapy progressed. Regarding predictive factors of response, the tumor type (aggressive pituitary tumor versus pituitary carcinoma) appears as the strongest predictor of response to ICIs. To date, no predictor of response to anti-angiogenic drugs in the treatment of pituitary carcinomas and aggressive pituitary tumors has been identified. The interest of BZV add-on to first- or second-line chemotherapy warrants further investigation. In addition, we discuss perspectives regarding the TME-targeting in aggressive pituitary tumors and pituitary carcinomas, including perspectives on immunotherapy, anti-angiogenic drugs, as well as on other TME components, namely stromal cells, extracellular matrix, and secreted molecules.
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Affiliation(s)
- Mirela-Diana Ilie
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, "C.I. Parhon" National Institute of Endocrinology, Bucharest, Romania
| | - Dario De Alcubierre
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Anna Lucia Carretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Emmanuel Jouanneau
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Neurosurgery Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Gérald Raverot
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France.
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17
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Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Mary Lee GS, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, Braun DA. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma. Cancer Immunol Res 2023; 11:1114-1124. [PMID: 37279009 PMCID: PMC10526700 DOI: 10.1158/2326-6066.cir-22-0996] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/04/2023] [Accepted: 06/02/2023] [Indexed: 06/07/2023]
Abstract
Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.
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Affiliation(s)
- Renee Maria Saliby
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Talal El Zarif
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Ziad Bakouny
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
- Department of Internal Medicine, Brigham and Women’s Hospital, Boston, MA, 02215, USA
| | - Valisha Shah
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Wanling Xie
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Ronan Flippot
- Department of Cancer Medicine, Gustave Roussy, Paris Saclay University, Villejuif, France
| | - Thomas Denize
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - M. Harry Kane
- Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA
| | - Katrine N. Madsen
- Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA
| | - Miriam Ficial
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Laure Hirsch
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Xiao X. Wei
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - John A. Steinharter
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
- Larner College of Medicine, University of Vermont, Burlington, VT, 05405, USA
| | - Lauren C. Harshman
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
- Surface Oncology, Cambridge MA 02139, USA
| | - Ulka N. Vaishampayan
- University of Michigan/Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201 USA
| | - Mariano Severgnini
- Center for Immuno-Oncology Immune Assessment Laboratory at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA
| | - David F. McDermott
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Gwo-Shu Mary Lee
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Wenxin Xu
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Eliezer M. Van Allen
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Bradley A. McGregor
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Toni K. Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
| | - Rana R. McKay
- Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA
| | - David A. Braun
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA
- Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA
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Philip AK, Samuel BA, Bhatia S, Khalifa SAM, El-Seedi HR. Artificial Intelligence and Precision Medicine: A New Frontier for the Treatment of Brain Tumors. Life (Basel) 2022; 13:24. [PMID: 36675973 PMCID: PMC9866715 DOI: 10.3390/life13010024] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/08/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Brain tumors are a widespread and serious neurological phenomenon that can be life- threatening. The computing field has allowed for the development of artificial intelligence (AI), which can mimic the neural network of the human brain. One use of this technology has been to help researchers capture hidden, high-dimensional images of brain tumors. These images can provide new insights into the nature of brain tumors and help to improve treatment options. AI and precision medicine (PM) are converging to revolutionize healthcare. AI has the potential to improve cancer imaging interpretation in several ways, including more accurate tumor genotyping, more precise delineation of tumor volume, and better prediction of clinical outcomes. AI-assisted brain surgery can be an effective and safe option for treating brain tumors. This review discusses various AI and PM techniques that can be used in brain tumor treatment. These new techniques for the treatment of brain tumors, i.e., genomic profiling, microRNA panels, quantitative imaging, and radiomics, hold great promise for the future. However, there are challenges that must be overcome for these technologies to reach their full potential and improve healthcare.
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Affiliation(s)
- Anil K. Philip
- School of Pharmacy, University of Nizwa, Birkat Al Mouz, Nizwa 616, Oman
| | - Betty Annie Samuel
- School of Pharmacy, University of Nizwa, Birkat Al Mouz, Nizwa 616, Oman
| | - Saurabh Bhatia
- Natural and Medical Science Research Center, University of Nizwa, Birkat Al Mouz, Nizwa 616, Oman
| | - Shaden A. M. Khalifa
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden
| | - Hesham R. El-Seedi
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
- Pharmacognosy Group, Department of Pharmaceutical Biosciences, BMC, Uppsala University, SE-751 24 Uppsala, Sweden
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu Education Department, Jiangsu University, Nanjing 210024, China
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A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR). ESMO Open 2022; 7:100592. [PMID: 36502778 PMCID: PMC9808456 DOI: 10.1016/j.esmoop.2022.100592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/07/2022] [Accepted: 08/23/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV). PATIENTS AND METHODS Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value. RESULTS The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6). CONCLUSIONS The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.
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Nagane M, Ichimura K, Onuki R, Narushima D, Honda-Kitahara M, Satomi K, Tomiyama A, Arai Y, Shibata T, Narita Y, Uzuka T, Nakamura H, Nakada M, Arakawa Y, Ohnishi T, Mukasa A, Tanaka S, Wakabayashi T, Aoki T, Aoki S, Shibui S, Matsutani M, Ishizawa K, Yokoo H, Suzuki H, Morita S, Kato M, Nishikawa R. Bevacizumab beyond Progression for Newly Diagnosed Glioblastoma (BIOMARK): Phase II Safety, Efficacy and Biomarker Study. Cancers (Basel) 2022; 14:cancers14225522. [PMID: 36428615 PMCID: PMC9688169 DOI: 10.3390/cancers14225522] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/27/2022] [Accepted: 11/04/2022] [Indexed: 11/12/2022] Open
Abstract
We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.
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Affiliation(s)
- Motoo Nagane
- Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo 181-8611, Japan
- Correspondence: ; Tel.: +81-422-47-5511
| | - Koichi Ichimura
- Department of Brain Disease Translational Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Ritsuko Onuki
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Daichi Narushima
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Mai Honda-Kitahara
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Kaishi Satomi
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Arata Tomiyama
- Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yasuhito Arai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Takeo Uzuka
- Department of Neurosurgery, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Hideo Nakamura
- Department of Neurosurgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8555, Japan
| | - Mitsutoshi Nakada
- Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan
| | - Yoshiki Arakawa
- Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Takanori Ohnishi
- Department of Neurosurgery, Graduate School of Medicine, Ehime University, Ehime 790-0052, Japan
| | - Akitake Mukasa
- Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Shota Tanaka
- Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Toshihiko Wakabayashi
- Department of Neurosurgery, Graduate School of Medicine, Nagoya University, Aichi 464-8601, Japan
| | - Tomokazu Aoki
- Department of Neurosurgery, Kyoto Medical Center, Kyoto 612-8555, Japan
| | - Shigeki Aoki
- Department of Radiology, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Soichiro Shibui
- Department of Neurosurgery, Teikyo University Hospital, Kawasaki 213-8507, Japan
| | - Masao Matsutani
- Department of Neurosurgery, Kurosawa Hospital, Gunma 370-1203, Japan
| | - Keisuke Ishizawa
- Department of Pathology, Saitama Medical University, Saitama 350-0495, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Graduate School of Medicine, Gunma University, Gunma 371-8511, Japan
| | - Hiroyoshi Suzuki
- Department of Pathology and Laboratory Medicine, National Hospital Organization Sendai Medical Center, Miyagi 983-8520, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Mamoru Kato
- Division of Bioinformatics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Ryo Nishikawa
- Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama 350-1298, Japan
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21
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Wang CW, Chang CC, Lee YC, Lin YJ, Lo SC, Hsu PC, Liou YA, Wang CH, Chao TK. Weakly supervised deep learning for prediction of treatment effectiveness on ovarian cancer from histopathology images. Comput Med Imaging Graph 2022; 99:102093. [PMID: 35752000 DOI: 10.1016/j.compmedimag.2022.102093] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 05/13/2022] [Accepted: 06/03/2022] [Indexed: 11/30/2022]
Abstract
Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70 % of advanced patients are with recurrent cancer and decease. Surgical debulking of tumors following chemotherapy is the conventional treatment for advanced carcinoma, but patients with such treatment remain at great risk for recurrence and developing drug resistance, and only about 30 % of the women affected will be cured. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Considering the cost, potential toxicity, and finding that only a portion of patients will benefit from these drugs, the identification of new predictive method for the treatment of ovarian cancer remains an urgent unmet medical need. In this study, we develop weakly supervised deep learning approaches to accurately predict therapeutic effect for bevacizumab of ovarian cancer patients from histopathological hematoxylin and eosin stained whole slide images, without any pathologist-provided locally annotated regions. To the authors' best knowledge, this is the first model demonstrated to be effective for prediction of the therapeutic effect of patients with epithelial ovarian cancer to bevacizumab. Quantitative evaluation of a whole section dataset shows that the proposed method achieves high accuracy, 0.882 ± 0.06; precision, 0.921 ± 0.04, recall, 0.912 ± 0.03; F-measure, 0.917 ± 0.07 using 5-fold cross validation and outperforms two state-of-the art deep learning approaches Coudray et al. (2018), Campanella et al. (2019). For an independent TMA testing set, the three proposed methods obtain promising results with high recall (sensitivity) 0.946, 0.893 and 0.964, respectively. The results suggest that the proposed method could be useful for guiding treatment by assisting in filtering out patients without positive therapeutic response to suffer from further treatments while keeping patients with positive response in the treatment process. Furthermore, according to the statistical analysis of the Cox Proportional Hazards Model, patients who were predicted to be invalid by the proposed model had a very high risk of cancer recurrence (hazard ratio = 13.727) than patients predicted to be effective with statistical signifcance (p < 0.05).
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan; Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Cheng-Chang Chang
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Ching Lee
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Yi-Jia Lin
- Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan; Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan
| | - Shih-Chang Lo
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Po-Chao Hsu
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Yi-An Liou
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Chih-Hung Wang
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan; Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan.
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22
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Mitsuma A, Ito Y, Shimokata T, Tanaka C, Uehara K, Nakayama G, Terasaki H, Ando Y. Direct Observation of Retinal Microvessels in Cancer Patients After Systemic Administration of Bevacizumab and Oxaliplatin. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:330-335. [PMID: 35530649 PMCID: PMC9066537 DOI: 10.21873/cdp.10113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/21/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Antiangiogenic chemotherapy is the backbone of the various anticancer therapies. To date no practical biomarker predicting their antitumor effects and toxicity has been reported. We aimed to determine the feasibility of direct retinal observation as a practical biomarker in antiangiogenic chemotherapy. PATIENTS AND METHODS By direct retinal observation using a nonmydriatic retinal camera, we measured retinal microvessel diameters in 10 patients with colorectal cancer before and after intravenous infusion of bevacizumab and oxaliplatin. All patients also received oral capecitabine during their therapy. RESULTS Retinal microvessel diameters were decreased from baseline temporarily by 14.5±6.5% after infusion of bevacizumab and oxaliplatin in five patients who responded to treatment and 8.8±6.2% in the other five patients (p=0.008). CONCLUSION Measurement of retinal microvessel diameters by direct observation appears to be feasible in patients receiving systemic chemotherapy. The decrease of retinal microvessel diameters might indicate improved tumor response to treatment with bevacizumab-containing systemic chemotherapy.
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Affiliation(s)
- Ayako Mitsuma
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Yasuki Ito
- Department of Ophthalmology, Nagoya University Hospital, Nagoya, Japan
- Department of Ophthalmology, Fujita Health University School of Medicine, Aichi, Japan
| | - Tomoya Shimokata
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Kay Uehara
- Division of Surgical Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Hiroko Terasaki
- Department of Ophthalmology, Nagoya University Hospital, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
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23
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van Dijk E, van Werkhoven E, Asher R, Mooi JK, Espinoza D, van Essen HF, van Tinteren H, van Grieken NCT, Punt CJA, Tebbutt NC, Ylstra B. Predictive value of chromosome 18q11.2-q12.1 loss for benefit from bevacizumab in metastatic colorectal cancer; a post-hoc analysis of the randomized phase III-trial AGITG-MAX. Int J Cancer 2022; 151:1166-1174. [PMID: 35489024 PMCID: PMC9545440 DOI: 10.1002/ijc.34061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/07/2022] [Accepted: 04/12/2022] [Indexed: 11/24/2022]
Abstract
The VEGF‐A monoclonal antibody bevacizumab is currently recommended for first‐line treatment of all metastatic colorectal cancer (mCRC) patients. Cost‐benefit ratio and side‐effects however necessitate patient selection. A large retrospective yet nonrandomized study showed that patients with loss of chromosome 18q11.2‐q12.1 in the tumor and treated with bevacizumab have 3 months improved median progression‐free (PFS) and overall survival (OS) benefit compared to patients without this loss and/or treatment modality. Implementation for loss of chromosome 18q11.2‐q12.1 as a marker in clinical practice mandates evidence in a randomized controlled trial for bevacizumab. Of the trials with randomization of chemotherapy vs chemotherapy with bevacizumab, the AGITG‐MAX trial was the only one with tumor materials available. Chromosome 18q11.2‐q12.1 copy number status was measured for 256 AGITG‐MAX trial patients and correlated with PFS according to a predefined analysis plan with marker‐treatment interaction as the primary end‐point. Chromosome 18q11.2‐q12.1 losses were detected in 71% of patients (181/256) characteristic for mCRC. Consistent with the nonrandomized study, significant PFS benefit of bevacizumab was observed in patients with chromosome 18q11.2‐q12.1 loss (P = .009), and not in patients without 18q loss (P = .67). Although significance for marker‐treatment interaction was not reached (Pinteraction = .28), hazard ratio and 95% confidence interval of this randomized cohort (HRinteraction = 0.72; 95% CI = 0.39‐1.32) shows striking overlap with the nonrandomized study cohorts (HRinteraction = 0.41; 95% CI = 0.32‐0.8) supported by a nonsignificant Cochrane χ2 test (P = .11) for heterogeneity. We conclude that post hoc analysis of the AGITG‐MAX RCT provides supportive evidence for chromosome 18q11.2‐q12.1 as a predictive marker for bevacizumab in mCRC patients.
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Affiliation(s)
- Erik van Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Erik van Werkhoven
- Biometrics Department, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Rebecca Asher
- Department of Biostatistics, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
| | - Jennifer K Mooi
- Olivia Newton-John Cancer Research Institute, Heidelberg; Department of Medicine, University of Melbourne, Melbourne, Australia.,Peter MacCallum Cancer Institute, Melbourne, Australia
| | - David Espinoza
- Department of Biostatistics, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
| | - Hendrik F van Essen
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Harm van Tinteren
- Trial and Datacenter, Princess Máxima Center for pedeatric oncology, Utrecht, The Netherlands
| | - Nicole C T van Grieken
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Epidemiology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Heidelberg, Australia.,Department of Surgery, University of Melbourne
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
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24
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Zhang X, Hong R, Bei L, Yang J, Zhao X, Hu Z, Chen L, Meng H, Zhang Q, Niu G, Yue Y, Ke C. Selenium binding protein 1 inhibits tumor angiogenesis in colorectal cancers by blocking the Delta-like ligand 4/Notch1 signaling pathway. Transl Oncol 2022; 18:101365. [PMID: 35158204 PMCID: PMC8850798 DOI: 10.1016/j.tranon.2022.101365] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/27/2022] [Accepted: 02/06/2022] [Indexed: 01/03/2023] Open
Abstract
SELENBP1 localizes to vessels and is suppressed in tumor vessels. SELENBP1 inhibits in vivo and in vitro angiogenesis. SELENBP1 antagonizes tumor angiogenesis by blocking the DLL4/Notch1 signaling pathway. SELENBP1 is a candidate target to treat bevacizumab-resistance in colorectal cancer. Background Selenium binding protein 1 (SELENBP1) is frequently downregulated in malignancies such as colorectal cancer (CRC), however, whether it is involved in tumor angiogenesis is still unknown. Methods We analyzed the expression and localization of SELENBP1 in vessels from CRC and neighboring tissues. We investigated the in vitro and in vivo activity of SELENBP1 in angiogenesis and explored the underlying mechanism. Results SELENBP1 was localized to endothelial cells in addition to glandular cells, while its vascular expression was decreased in tumor vessels compared to that in vessels from neighboring non-tumor tissues. Gain-of-function and loss-of-function experiments demonstrated that SELENBP1 inhibited angiogenesis in vitro, and blocked communications between HUVECs and CRC cells. Overexpression of SELENBP1 in CRC cells inhibited tumor growth and angiogenesis, and enhanced bevacizumab-sensitivity in a mouse subcutaneous xenograft model. Mechanic analyses revealed that SELENBP1 may suppress tumor angiogenesis by binding with Delta-like ligand 4 (DLL4) and antagonizing the DLL4/Notch1 signaling pathway. The inhibitory effects of SELENBP1 on in vitro angiogenesis could largely be rescued by DLL4. Conclusion These results revealed a novel role of SELENBP1 as a potential tumor suppressor that antagonizes tumor angiogenesis in CRC by intervening the DLL4/Notch1 signaling pathway.
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Affiliation(s)
- Xiaotian Zhang
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China
| | - Runqi Hong
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China
| | - Lanxin Bei
- Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ju Yang
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Xiaomei Zhao
- Department of Medicine, Dongying New District Hospital, Dongying, Shandong 257000, China
| | - Zhiqing Hu
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China
| | - Liang Chen
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China
| | - He Meng
- Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qian Zhang
- Department of Orthopedics, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221300, China
| | - Gengming Niu
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China.
| | - Ying Yue
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China.
| | - Chongwei Ke
- Department of General Surgery, Shanghai Fifth People's Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai 200240, China.
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25
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Wang CW, Lee YC, Chang CC, Lin YJ, Liou YA, Hsu PC, Chang CC, Sai AKO, Wang CH, Chao TK. A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker. Cancers (Basel) 2022; 14:cancers14071651. [PMID: 35406422 PMCID: PMC8996991 DOI: 10.3390/cancers14071651] [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: 01/27/2022] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer is a common malignant gynecological disease. Molecular target therapy, i.e., antiangiogenesis with bevacizumab, was found to be effective in some patients of epithelial ovarian cancer (EOC). Although careful patient selection is essential, there are currently no biomarkers available for routine therapeutic usage. To the authors’ best knowledge, this is the first automated precision oncology framework to effectively identify and select EOC and peritoneal serous papillary carcinoma (PSPC) patients with positive therapeutic effect. From March 2013 to January 2021, we have a database, containing four kinds of immunohistochemical tissue samples, including AIM2, c3, C5 and NLRP3, from patients diagnosed with EOC and PSPC and treated with bevacizumab in a hospital-based retrospective study. We developed a hybrid deep learning framework and weakly supervised deep learning models for each potential biomarker, and the experimental results show that the proposed model in combination with AIM2 achieves high accuracy 0.92, recall 0.97, F-measure 0.93 and AUC 0.97 for the first experiment (66% training and 34%testing) and high accuracy 0.86 ± 0.07, precision 0.9 ± 0.07, recall 0.85 ± 0.06, F-measure 0.87 ± 0.06 and AUC 0.91 ± 0.05 for the second experiment using five-fold cross validation, respectively. Both Kaplan-Meier PFS analysis and Cox proportional hazards model analysis further confirmed that the proposed AIM2-DL model is able to distinguish patients gaining positive therapeutic effects with low cancer recurrence from patients with disease progression after treatment (p < 0.005).
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan;
| | - Yu-Ching Lee
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan;
| | - Cheng-Chang Chang
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei 11490, Taiwan; (C.-C.C.); (P.-C.H.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-Jia Lin
- Department of Pathology, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-An Liou
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Po-Chao Hsu
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei 11490, Taiwan; (C.-C.C.); (P.-C.H.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chun-Chieh Chang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Aung-Kyaw-Oo Sai
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Chih-Hung Wang
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Taipei 11490, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence:
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26
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Coltelli L, Allegrini G, Orlandi P, Finale C, Fontana A, Masini LC, Scalese M, Arrighi G, Barletta MT, De Maio E, Banchi M, Fini E, Guidi P, Frenzilli G, Donati S, Giovannelli S, Tanganelli L, Salvadori B, Livi L, Meattini I, Pazzagli I, Di Lieto M, Pistelli M, Casadei V, Ferro A, Cupini S, Orlandi F, Francesca D, Lorenzini G, Barellini L, Falcone A, Cosimi A, Bocci G. A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients. NPJ Breast Cancer 2022; 8:33. [PMID: 35314692 PMCID: PMC8938486 DOI: 10.1038/s41523-022-00400-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 02/07/2022] [Indexed: 11/18/2022] Open
Abstract
To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5–0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5–1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.
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27
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Stegelmeier AA, Santry LA, Guilleman MM, Matuszewska K, Minott JA, Yates JGE, Stevens BAY, Thomas SP, Vanderkamp S, Hanada K, Pei Y, Rghei AD, van Vloten JP, Pereira M, Thompson B, Major PP, Petrik JJ, Bridle BW, Wootton SK. AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma. Biomedicines 2022; 10:biomedicines10020362. [PMID: 35203573 PMCID: PMC8962366 DOI: 10.3390/biomedicines10020362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 11/16/2022] Open
Abstract
Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.
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Affiliation(s)
- Ashley A. Stegelmeier
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Lisa A. Santry
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Matthew M. Guilleman
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Kathy Matuszewska
- Department of Biomedical Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (K.M.); (M.P.); (J.J.P.)
| | - Jessica A. Minott
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Jacob G. E. Yates
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Brenna A. Y. Stevens
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Sylvia P. Thomas
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Sierra Vanderkamp
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Kiersten Hanada
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Yanlong Pei
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Amira D. Rghei
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Jacob P. van Vloten
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Madison Pereira
- Department of Biomedical Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (K.M.); (M.P.); (J.J.P.)
| | | | - Pierre P. Major
- Juravinski Cancer Centre, 699 Concession Street, Hamilton, ON L8V 5C2, Canada;
| | - James J. Petrik
- Department of Biomedical Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada; (K.M.); (M.P.); (J.J.P.)
| | - Byram W. Bridle
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
| | - Sarah K. Wootton
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada; (A.A.S.); (L.A.S.); (M.M.G.); (J.A.M.); (J.G.E.Y.); (B.A.Y.S.); (S.P.T.); (S.V.); (K.H.); (Y.P.); (A.D.R.); (J.P.v.V.); (B.W.B.)
- Correspondence: ; Tel.: +1-519-824-4210 (ext. 54729)
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Moy RH, Greally M, Chou JF, Li J, Desai AM, Chalasani SB, Won E, Kelsen DP, Ilson DH, Janjigian YY, Capanu M, Ku GY. Phase I/Ib study of crenolanib with ramucirumab and paclitaxel as second-line therapy for advanced esophagogastric adenocarcinoma. Cancer Chemother Pharmacol 2022; 89:255-265. [PMID: 35066693 DOI: 10.1007/s00280-021-04384-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/10/2021] [Indexed: 01/25/2023]
Abstract
PURPOSE Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab. METHODS Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD. RESULTS We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor. CONCLUSIONS The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID. CLINICAL TRIAL REGISTRATION NCT03193918. June 19, 2017.
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Affiliation(s)
- Ryan H Moy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Megan Greally
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jia Li
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Avni M Desai
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Sree B Chalasani
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Elizabeth Won
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - David P Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - David H Ilson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Yelena Y Janjigian
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Geoffrey Y Ku
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA.
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VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer. Sci Rep 2022; 12:1238. [PMID: 35075138 PMCID: PMC8786898 DOI: 10.1038/s41598-021-03952-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023] Open
Abstract
The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.
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Zhang T, Zhang L, Gao Y, Wang Y, Liu Y, Zhang H, Wang Q, Hu F, Li J, Tan J, Wang DD, Gires O, Lin PP, Li B. Role of aneuploid circulating tumor cells and CD31 + circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC. Mol Oncol 2021; 15:2891-2909. [PMID: 34455700 PMCID: PMC8564645 DOI: 10.1002/1878-0261.13092] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/23/2021] [Indexed: 12/18/2022] Open
Abstract
Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)– CTCs and CD31+ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM+/Vim+ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM–/Vim– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post‐therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.
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Affiliation(s)
- Tongmei Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Lina Zhang
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yuan Gao
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Ying Wang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yanxia Liu
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Hongmei Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Qunhui Wang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Fanbin Hu
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Jie Li
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Jinjing Tan
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | | | - Olivier Gires
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU Munich, Germany
| | | | - Baolan Li
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
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Ribatti D, Solimando AG, Pezzella F. The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer. Cancers (Basel) 2021; 13:cancers13143433. [PMID: 34298648 PMCID: PMC8304542 DOI: 10.3390/cancers13143433] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/24/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: ; Tel.: +39-080-547832
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, 70124 Bari, Italy;
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy
| | - Francesco Pezzella
- Nuffield Division of Laboratory Science, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX39DU, UK;
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Conde E, Earl J, Crespo-Toro L, Blanco-Agudo C, Ramos-Muñoz E, Rodríguez-Serrano EM, Martínez Ávila JC, Salinas-Muñoz L, Serrano-Huertas S, Ferreiro R, Rodriguez-Garrote M, Sainz B, Massuti B, Alfonso PG, Benavides M, Aranda E, García-Bermejo ML, Carrato A. Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study. Cancers (Basel) 2021; 13:cancers13071710. [PMID: 33916610 PMCID: PMC8038427 DOI: 10.3390/cancers13071710] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Biomarkers able to predict response and toxicity upon regorafenib therapy for colorectal cancer (CRC) are critical for treatment choice, particularly relevant in fragile patients. Here, we validated for the first time 18 distinct microRNAs (miRNAs) detected in serum and primary tumor samples, three germline single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) genes, and low levels of Notch 1 expression in the primary tumor as predictive biomarkers of different features. Specifically, these markers were associated with a favorable response to treatment, disease stage, and relapse, as well as the appearance of asthenia. Therefore, these markers can be potentially useful biomarkers for patient stratification and for providing a more personalized and effective therapeutic strategy in fragile patients, while limiting the appearance of adverse effects. Abstract First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.
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Affiliation(s)
- Elisa Conde
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Lorena Crespo-Toro
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Carolina Blanco-Agudo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - E. Macarena Rodríguez-Serrano
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Jose Carlos Martínez Ávila
- Departamento de Matemática Aplicada y Estadística, Facultad de Ciencias Económicas y Empresariales, Universidad San Pablo CEU, C/Julián Romea, 23, 28003 Madrid, Spain;
| | - Laura Salinas-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Silvia Serrano-Huertas
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
| | - Reyes Ferreiro
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Mercedes Rodriguez-Garrote
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
| | - Bruno Sainz
- Department of Biochemistry, Ramón y Cajal Health Research Institute (IRYCIS) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Universidad Autónoma de Madrid (UAM), CSIC-UAM, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain;
- Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer Area 3-IRYCIS, 28034 Madrid, Spain
| | - Bartomeu Massuti
- Oncology Department, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario de Alicante, Universidad Miguel Hernández, Pintor Baeza, 11, 03010 Alicante, Spain;
| | - Pilar García Alfonso
- Oncology Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Universitario Gregorio Marañón, Doctor Esquerdo 46, 28028 Madrid, Spain;
| | - Manuel Benavides
- Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain;
| | - Enrique Aranda
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
- Oncology Department, Instituto Maimonides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, University of Córdoba, IMIBIC, Av. Menéndez Pidal, s/n, 14004 Córdoba, Spain
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain; (E.C.); (L.C.-T.); (C.B.-A.); (E.R.-M.); (E.M.R.-S.); (L.S.-M.); (S.S.-H.)
- Correspondence: ; Tel.: +34-913-368-075
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; (J.E.); (R.F.); (M.R.-G.); (A.C.)
- Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;
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Li D, Finley SD. Mechanistic insights into the heterogeneous response to anti‐VEGF treatment in tumors. COMPUTATIONAL AND SYSTEMS ONCOLOGY 2021. [DOI: 10.1002/cso2.1013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Ding Li
- Department of Biomedical Engineering University of Southern California Los Angeles California USA
| | - Stacey D. Finley
- Departments of Biomedical Engineering, Quantitative and Computational Biology, and Chemical Engineering and Materials Science University of Southern California Los Angeles California USA
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Nakamoto S, Watanabe J, Ohtani S, Morita S, Ikeda M. Bevacizumab as First-line Treatment for HER2-negative Advanced Breast Cancer: Paclitaxel plus Bevacizumab Versus Other Chemotherapy. In Vivo 2021; 34:1377-1386. [PMID: 32354934 DOI: 10.21873/invivo.11917] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/06/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The efficacy of paclitaxel and bevacizumab (PB) compared with other chemotherapies in patients with human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer is unclear. PATIENTS AND METHODS We retrospectively investigated 301 patients with HER2- ABC who received first-line chemotherapy from January 2011 to December 2016. RESULTS We included 114 patients who received PB and 187 patients who received other chemotherapies. After propensity score matching, the PB group showed a significantly superior overall response rate (77.8% vs. 38.9%, p<0.0001) and median time to treatment failure (7.3 vs. 5.9 months, p=0.035). In subgroup analyses, PB improved the median overall survival of patients with pleural lesions or pulmonary lymphangiopathy (not reached vs. 18.9 months, p=0.037), and of patients with three or more metastatic sites without liver metastases, (48.0 vs. 27.3 months, p=0.015). CONCLUSION Compared with conventional chemotherapy, PB improved the overall response rate and time to treatment failure in patients with HER2- advanced breast cancer and improved overall survival in some patient subgroups.
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Affiliation(s)
- Shogo Nakamoto
- Department of Breast Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Shoichiro Ohtani
- Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiko Ikeda
- Department of Breast and Thyroid Gland Surgery, Fukuyama City Hospital, Fukuyama, Japan
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Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology 2021; 3:e27048. [PMID: 24605265 PMCID: PMC3937194 DOI: 10.4161/onci.27048] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 11/01/2013] [Indexed: 02/06/2023] Open
Abstract
In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.
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Affiliation(s)
- Erika Vacchelli
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | - Fernando Aranda
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | | | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 15, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
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Krüger K, Silwal-Pandit L, Wik E, Straume O, Stefansson IM, Borgen E, Garred Ø, Naume B, Engebraaten O, Akslen LA. Baseline microvessel density predicts response to neoadjuvant bevacizumab treatment of locally advanced breast cancer. Sci Rep 2021; 11:3388. [PMID: 33564016 PMCID: PMC7873274 DOI: 10.1038/s41598-021-81914-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/04/2021] [Indexed: 02/06/2023] Open
Abstract
A subset of breast cancer patients benefits from preoperative bevacizumab and chemotherapy, but validated predictive biomarkers are lacking. Here, we aimed to evaluate tissue-based angiogenesis markers for potential predictive value regarding response to neoadjuvant bevacizumab treatment in breast cancer. In this randomized 1:1 phase II clinical trial, 132 patients with large or locally advanced HER2-negative tumors received chemotherapy ± bevacizumab. Dual Factor VIII/Ki-67 immunohistochemical staining was performed on core needle biopsies at baseline and week 12. Microvessel density (MVD), proliferative microvessel density (pMVD; Factor VIII/Ki-67 co-expression), glomeruloid microvascular proliferation (GMP), and a gene expression angiogenesis signature score, were studied in relation to pathologic complete response (pCR), clinico-pathologic features and intrinsic molecular subtype. We found that high baseline MVD (by median) significantly predicted pCR in the bevacizumab-arm (odds ratio 4.9, P = 0.012). High pMVD, presence of GMP, and the angiogenesis signature score did not predict pCR, but were associated with basal-like (P ≤ 0.009) and triple negative phenotypes (P ≤ 0.041). pMVD and GMP did also associate with high-grade tumors (P ≤ 0.048). To conclude, high baseline MVD significantly predicted response to bevacizumab treatment. In contrast, pMVD, GMP, and the angiogenesis signature score, did not predict response, but associated with aggressive tumor features, including basal-like and triple-negative phenotypes.
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Affiliation(s)
- Kristi Krüger
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway
| | - Laxmi Silwal-Pandit
- Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Elisabeth Wik
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Oddbjørn Straume
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, Section for Oncology, University of Bergen, Bergen, Norway
| | - Ingunn M Stefansson
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Olav Engebraaten
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway.
- Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study. Gynecol Oncol 2021; 161:113-121. [PMID: 33541735 DOI: 10.1016/j.ygyno.2021.01.025] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/20/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P. METHODS TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. RESULTS Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. CONCLUSIONS This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.
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Gwak SJ, Che L, Yun Y, Lee M, Ha Y. Combination Therapy by Tissue-Specific Suicide Gene and Bevacizumab in Intramedullary Spinal Cord Tumor. Yonsei Med J 2020; 61:1042-1049. [PMID: 33251778 PMCID: PMC7700877 DOI: 10.3349/ymj.2020.61.12.1042] [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] [Received: 06/18/2020] [Revised: 09/11/2020] [Accepted: 10/19/2020] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Malignant gliomas are aggressive spinal cord tumors. In this study, we hypothesized that combination therapy using an anti-angiogenic agent, bevacizumab, and hypoxia-inducible glioblastoma-specific suicide gene could reduce tumor growth. MATERIALS AND METHODS In the present study, we evaluated the effect of combination therapy using bevacizumab and pEpo-NI2-SV-TK in reducing the proliferation of C6 cells and tumor growth in the spinal cord. Spinal cord tumor was generated by the injection of C6 cells into the T5 level of the spinal cord. Complexes of branched polyethylenimine (bPEI)/pEpo-NI2-SV-TK were injected into the spinal cord tumor. Bevacizumab was then administered by an intraperitoneal injection at a dose of 7 mg/kg. The anti-cancer effects of combination therapy were analyzed by histological analyses and magnetic resonance imaging (MRI). The Basso, Beattie and Bresnahan scale scores for all of the treatment groups were recorded every other day for 15 days to assess the rat hind-limb strength. RESULTS The complexes of bPEI/pEpo-NI2-SV-TK inhibited the viability of C6 cells in the hypoxia condition at 5 days after treatment with ganciclovir. Bevacizumab was decreased in the cell viability of human umbilical vein endothelial cells. Combination therapy reduced the tumor size by histological analyses and MRI. The combination therapy group showed improved hind-limb function compared to the other groups that were administered pEpo-NI2-SV-TK alone or bevacizumab alone. CONCLUSION This study suggests that combination therapy using bevacizumab with the pEpo-NI2-SV-TK therapeutic gene could be useful for increasing its therapeutic benefits for intramedullary spinal cord tumors.
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Affiliation(s)
- So Jung Gwak
- Department of Chemical Engineering, Wonkwang University, Iksan, Korea
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Lihua Che
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yeomin Yun
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Minhyung Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea
| | - Yoon Ha
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Leone JP, Emblem KE, Weitz M, Gelman RS, Schneider BP, Freedman RA, Younger J, Pinho MC, Sorensen AG, Gerstner ER, Harris G, Krop IE, Morganstern D, Sohl J, Hu J, Kasparian E, Winer EP, Lin NU. Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Res 2020; 22:131. [PMID: 33256829 PMCID: PMC7706261 DOI: 10.1186/s13058-020-01372-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/15/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We aimed to examine the safety and efficacy of bevacizumab and carboplatin in patients with breast cancer brain metastases. METHODS We enrolled patients with breast cancer and > 1 measurable new or progressive brain metastasis. Patients received bevacizumab 15 mg/kg intravenously (IV) on cycle 1 day 1 and carboplatin IV AUC = 5 on cycle 1 day 8. Patients with HER2-positive disease also received trastuzumab. In subsequent cycles, all drugs were administered on day 1 of each cycle. Contrast-enhanced brain MRI was performed at baseline, 24-96 h after the first bevacizumab dose (day + 1), and every 2 cycles. The primary endpoint was objective response rate in the central nervous system (CNS ORR) by composite criteria. Associations between germline VEGF single nucleotide polymorphisms (rs699947, rs2019063, rs1570360, rs833061) and progression-free survival (PFS) and overall survival (OS) were explored, as were associations between early (day + 1) MRI changes and outcomes. RESULTS Thirty-eight patients were enrolled (29 HER2-positive, 9 HER2-negative); all were evaluable for response. The CNS ORR was 63% (95% CI, 46-78). Median PFS was 5.62 months and median OS was 14.10 months. As compared with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, patients with ECOG PS 1-2 had significantly worse PFS and OS (all P < 0.01). No significant associations between VEGF genotypes or early MRI changes and clinical outcomes were observed. CONCLUSIONS The combination of bevacizumab and carboplatin results in a high rate of durable objective response in patients with brain metastases from breast cancer. This regimen warrants further investigation. TRIAL REGISTRATION NCT01004172 . Registered 28 October 2009.
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Affiliation(s)
- Jose Pablo Leone
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Kyrre E Emblem
- Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway
| | - Michelle Weitz
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Rebecca S Gelman
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | | | - Rachel A Freedman
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | | | - Marco C Pinho
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | | | | | - Ian E Krop
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Daniel Morganstern
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Jessica Sohl
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Jiani Hu
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Elizabeth Kasparian
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Eric P Winer
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Nancy U Lin
- Dana-Farber Cancer Institute, Dana-Farber/Brigham & Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA.
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Barat A, Smeets D, Moran B, Zhang W, Cao S, Das S, Klinger R, Betge J, Murphy V, Bacon O, Kay EW, Van Grieken NCT, Verheul HMW, Gaiser T, Schulte N, Ebert MP, Fender B, Hennessy BT, McNamara DA, O'Connor D, Gallagher WM, Cremolini C, Loupakis F, Parikh A, Mancao C, Ylstra B, Lambrechts D, Lenz HJ, Byrne AT, Prehn JHM. Combination of variations in inflammation- and endoplasmic reticulum-associated genes as putative biomarker for bevacizumab response in KRAS wild-type colorectal cancer. Sci Rep 2020; 10:9778. [PMID: 32555399 PMCID: PMC7299973 DOI: 10.1038/s41598-020-65869-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 05/05/2020] [Indexed: 12/30/2022] Open
Abstract
Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs. We further employed a machine learning approach to identify novel associations. In the APD cohort IL8 rs4073 any A carriers, compared to TT carriers, were associated with worse progression-free survival (PFS) (HR = 1.51, 95% CI:1.03-2.22, p-value = 0.037) and TBK1 rs7486100 TT carriers, compared to any A carriers, were associated with worse PFS in KRAS wild-type (wt) patients (HR = 1.94, 95% CI:1.04-3.61, p-value = 0.037), replicating previous findings. Machine learning identified novel associations in genes encoding the inflammasome protein NLRP1 and the ER protein Sarcalumenin (SRL). A negative association between PFS and carriers of any A at NLRP1 rs12150220 and AA for SRL rs13334970 in APD KRAS wild-type patients (HR = 4.44, 95% CI:1.23-16.13, p-value = 0.005), which validated in two independent clinical cohorts involving BVZ, MAVERICC and TRIBE. Our findings highlight a key role for inflammation and ER signalling underpinning BVZ + chemotherapy responsiveness.
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Affiliation(s)
- Ana Barat
- Centre for Systems Medicine and Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
| | | | - Bruce Moran
- UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Wu Zhang
- USC Norris Comprehensive Cancer Center, Los Angeles, USA
| | - Shu Cao
- USC Norris Comprehensive Cancer Center, Los Angeles, USA
| | - Sudipto Das
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Rut Klinger
- UCD, School of Biomolecular and Biomedical Science, Dublin, Ireland
| | - Johannes Betge
- Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, Heidelberg, Germany
| | | | - Orna Bacon
- Centre for Systems Medicine and Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | | | - Henk M W Verheul
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Timo Gaiser
- Institute of Pathology, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nadine Schulte
- Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bozena Fender
- OncoMark Ltd., NovaUCD, Belfield Innovation Park, Dublin, Ireland
| | - Bryan T Hennessy
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | | | - Darran O'Connor
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Chiara Cremolini
- Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Fotios Loupakis
- Oncology Unit, Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy
| | - Aparna Parikh
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, USA
| | - Christoph Mancao
- Oncology Biomarker Development, Genentech Inc., San Francisco, USA
| | - Bauke Ylstra
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | | | | | - Annette T Byrne
- Centre for Systems Medicine and Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jochen H M Prehn
- Centre for Systems Medicine and Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
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Coadjuvant Anti-VEGF A Therapy Improves Survival in Patients with Colorectal Cancer with Liver Metastasis: A Systematic Review. GASTROINTESTINAL DISORDERS 2020. [DOI: 10.3390/gidisord2020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: the presence of liver metastasis in colorectal cancer (CRC) remains one of the most significant prognostic factors. Objective: systematically review the results of studies evaluating the benefit of adding bevacizumab to a normal chemotherapy regime in the survival of patients with colorectal-cancer liver metastasis (CRLM). Search methods: Pubmed and Google Scholar databases were searched for eligible articles (from inception up to the 2 April 2019). Inclusion criteria: studies including patients with CRLM receiving anti-vascular endothelial growth factor (VEGF; bevacizumab) as treatment, overall survival as an outcome; regarding language restrictions, only articles in English were accepted. Main results: Eleven studies met the inclusion criteria. In 73% of these cases, chemotherapy with bevacizumab was an effective treatment modality for treating CRLM, and its administration significantly extended both overall survival (OS) and/or progression-free survival (PFS). Nevertheless, three articles showed no influence on survival rates of bevacizumab-associated chemotherapy. Author conclusions: It is necessary to standardize methodologies that aim to evaluate the impact of bevacizumab administration on the survival of patients with CRLM. Furthermore, follow-up time and the cause of a patient’s death should be recorded, specified, and cleared in order to better calculate the survival rate and provide a comparison between the produced literature.
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Expression of pro-angiogenic factors as potential biomarkers in experimental models of colon cancer. J Cancer Res Clin Oncol 2020; 146:1427-1440. [PMID: 32300865 DOI: 10.1007/s00432-020-03186-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/14/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE RAS mutational status in colorectal cancer (CRC) represents a predictive biomarker of response to anti-EGFR therapy, but to date it cannot be considered an appropriate biomarker of response to anti-VEGF therapy. To elucidate the function of K-Ras in promoting angiogenesis, the effect of conditioned media from KRAS mutated and wild type colon cancer cell lines on HUVECs tubule formation ability and the correspondent production of pro-angiogenic factors have been evaluated by a specific ELISA assay. METHODS Ras-activated signaling pathways were compared by western blot analysis and RTq-PCR. In addition, VEGF, IL-8, bFGF and HIF-1α expression was determined in K-RAS silenced cells. Furthermore, we conducted an observational study in a cohort of RAS mutated metastatic CRC patients, treated with first-line bevacizumab-based regimens, evaluating VEGF-A and IL-8 plasma levels at baseline, and during treatment. RESULTS K-RAS promotes VEGF production by cancer cell lines. At the transcriptional level, this is reflected to a K-RAS dependent HIF-1α over-expression. Moreover, the HIF-1α, VEGF and FGF expression inhibition in KRAS knocked cells confirmed these results. Within the clinical part, no statistically significant correlation has been found between progression-free survival (PFS) and VEGF-A/IL-8 levels, but we cannot exclude that these biomarkers could be further investigated as predictive or prognostic biomarkers in this setting. CONCLUSION Our study confirmed the direct involvement of K-Ras in promoting angiogenesis into colon cancer cell lines.
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Lv P, Shi F, Chen X, Xu L, Wang C, Tian S, Yang H, Hou L. Tea polyphenols inhibit the growth and angiogenesis of breast cancer xenografts in a mouse model. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2020. [DOI: 10.1016/j.jtcms.2020.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, Chinot OL. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020; 86:102017. [PMID: 32335505 DOI: 10.1016/j.ctrv.2020.102017] [Citation(s) in RCA: 700] [Impact Index Per Article: 140.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/20/2020] [Accepted: 03/22/2020] [Indexed: 01/01/2023]
Abstract
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
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Affiliation(s)
- Josep Garcia
- Global Clinical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
| | | | | | | | - Robert L Coleman
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas, MD Anderson Cancer Center, TX, USA
| | - Regula Deurloo
- Oncology Biomarker Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - Olivier L Chinot
- Aix-Marseille University, Assistance Publique-Hopitaux de Marseille, Centre Hospitalo-Universitaire Timone, Service de Neuro-Oncologie, Marseille, France
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Nelson T, Hu J, Bannykh S, Fan X, Rudnick J, Vail E. Clinical response to pazopanib in a patient with endolymphatic sac tumor not associated with von Hippel-Lindau syndrome. CNS Oncol 2020; 9:CNS50. [PMID: 32141326 PMCID: PMC7163403 DOI: 10.2217/cns-2019-0019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Endolymphatic sac tumors (ELSTs) are rare, locally invasive, vascular tumors of the temporal bone. These lesions are associated with von Hippel-Lindau syndrome but may arise sporadically. Early surgical intervention is recommended to prevent permanent neurologic deficits; however, many ELSTs are unresectable or are subtotally resected due to neurovascular compromise. Chemotherapeutic salvage therapy in trials of neoplasms of associated syndromes has targeted angiogenesis with variable response. We present the case of a sporadic ELST, previously minimally responsive to bevacizumab, treated with pazopanib, a multi-kinase inhibitor and antiangiogenic, with good response. Cases such as our patient may demonstrate the utility of novel antiangiogenics in the treatment of these rare neoplasms, particularly when the tumor is unresectable or necessitates subtotal resection.
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Affiliation(s)
- Thomas Nelson
- Department of Neurology, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, Suite A6600, Los Angeles, CA 90048, USA
| | - Jethro Hu
- Division of Neuro-Oncology, Department of Neurology, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, 6th Floor, Los Angeles, CA 90048, USA
| | - Serguei Bannykh
- Division of Neuropathology, Department of Pathology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Xuemo Fan
- Division of Neuropathology, Department of Pathology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Jeremy Rudnick
- Division of Neuro-Oncology, Department of Neurology, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, 6th Floor, Los Angeles, CA 90048, USA
| | - Eric Vail
- Division of Molecular Pathology, Department of Pathology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
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Van Cutsem E, Muro K, Cunningham D, Bodoky G, Sobrero A, Cascinu S, Ajani J, Oh SC, Al-Batran SE, Wainberg ZA, Wijayawardana SR, Melemed S, Ferry D, Hozak RR, Ohtsu A. Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study. Eur J Cancer 2020; 127:150-157. [PMID: 32014812 DOI: 10.1016/j.ejca.2019.10.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/21/2019] [Accepted: 10/27/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.
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Affiliation(s)
- E Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg, Leuven and KULeuven, Leuven, Belgium.
| | - K Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | | | - G Bodoky
- Department of Oncology, St. László Hospital, Budapest, Hungary
| | - A Sobrero
- Medical Oncology, IRCCS Ospedale San Martino IST, Genova, Italy
| | - S Cascinu
- Department of Medical Oncology, Università Politecnica Delle Marche, Ancona, Italy
| | - J Ajani
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - S C Oh
- Korea University Guro Hospital, Seoul, South Korea
| | - S E Al-Batran
- Institute of Clinical Cancer Research (IKF), UCT- University Cancer Center, Frankfurt, Germany
| | - Z A Wainberg
- Medical Hematology and Oncology, University of California Los Angeles, Los Angeles, CA, USA
| | | | - S Melemed
- Eli Lilly and Company, Indianapolis, IN, USA
| | - D Ferry
- Eli Lilly and Company, Bridgewater, NJ, USA
| | - R R Hozak
- Eli Lilly and Company, Indianapolis, IN, USA
| | - A Ohtsu
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Neuropilin: Handyman and Power Broker in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1223:31-67. [PMID: 32030684 DOI: 10.1007/978-3-030-35582-1_3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Neuropilin-1 and neuropilin-2 form a small family of transmembrane receptors, which, due to the lack of a cytosolic protein kinase domain, act primarily as co-receptors for various ligands. Performing at the molecular level both the executive and organizing functions of a handyman as well as of a power broker, they are instrumental in controlling the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. In this setting, the various neuropilin ligands and interaction partners on various cells of the tumor microenvironment, such as cancer cells, endothelial cells, cancer-associated fibroblasts, and immune cells, are surveyed. The suitability of various neuropilin-targeting substances and the intervention in neuropilin-mediated interactions is considered as a possible building block of tumor therapy.
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Spagnuolo A, Palazzolo G, Sementa C, Gridelli C. Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer. Expert Opin Pharmacother 2020; 21:491-506. [DOI: 10.1080/14656566.2020.1713092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- A Spagnuolo
- Division of Medical Oncology, ‘S. G. Moscati’ Hospital, Avellino, Italy
| | - G Palazzolo
- Division of Medical Oncology, “ULSS 15 Cittadella”, Cittadella, Padova, Italy
| | - C Sementa
- Division of Legal Medicine, ‘S. G. Moscati’ Hospital, Avellino, Italy
| | - C Gridelli
- Division of Medical Oncology, ‘S. G. Moscati’ Hospital, Avellino, Italy
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Karn T, Meissner T, Weber KE, Solbach C, Denkert C, Engels K, Fasching PA, Sinn BV, Schrader I, Budczies J, Marmé F, Müller V, Holtrich U, Gerber B, Schem C, Young BM, Hanusch C, Stickeler E, Huober J, van Mackelenbergh M, Leyland-Jones B, Fehm T, Nekljudova V, Untch M, Loibl S. A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial. Clin Cancer Res 2020; 26:1896-1904. [PMID: 31932495 DOI: 10.1158/1078-0432.ccr-19-1954] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/19/2019] [Accepted: 01/08/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. EXPERIMENTAL DESIGN We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. RESULTS We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). CONCLUSIONS Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.
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Affiliation(s)
- Thomas Karn
- Goethe University Hospital Frankfurt, Frankfurt, Germany.
| | | | | | | | | | - Knut Engels
- Goethe University Hospital Frankfurt, Frankfurt, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Germany
| | | | - Iris Schrader
- Gynäkologisch-Onkologische Praxis Hannover, Hannover, Germany
| | | | | | - Volkmar Müller
- University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf, Germany
| | - Uwe Holtrich
- Goethe University Hospital Frankfurt, Frankfurt, Germany
| | | | | | | | | | | | | | | | | | - Tanja Fehm
- University Hospital Tübingen, Tübingen, Germany
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Miyagawa Y, Yanai A, Yanagawa T, Inatome J, Egawa C, Nishimukai A, Takamoto K, Morimoto T, Kikawa Y, Suwa H, Taji T, Yamaguchi A, Okada Y, Sata A, Fukui R, Bun A, Ozawa H, Higuchi T, Fujimoto Y, Imamura M, Miyoshi Y. Baseline neutrophil-to-lymphocyte ratio and c-reactive protein predict efficacy of treatment with bevacizumab plus paclitaxel for locally advanced or metastatic breast cancer. Oncotarget 2020; 11:86-98. [PMID: 32002126 PMCID: PMC6967770 DOI: 10.18632/oncotarget.27423] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/21/2019] [Indexed: 01/05/2023] Open
Abstract
The effect of bevacizumab plus paclitaxel therapy on progression-free survival (PFS) is prominent; however, no overall survival (OS) benefit has been demonstrated. Our aim was to study the predictive efficacy of peripheral immune-related parameters, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in locally advanced and metastatic breast cancers. A total of 179 patients treated with bevacizumab plus paclitaxel were recruited from three institutes in the test cohort. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/μL, and 1.0 mg/dL, respectively, and baseline values of these factors were measured. The PFS of patients with NLR-low was significantly longer than that of patients with -high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.48, 95% confidence interval (95% CI), 0.31–0.73; p = 0.0004). OS of patients with NLR-low was significantly better than those with-high (22.2 vs. 13.5 months; HR, 0.57, 95% CI, 0.39–0.83; p = 0.0032). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with patients with -high (HR, 0.44, 95% CI, 0.28–0.68; p = 0.0001 and HR, 0.39, 95% CI, 0.26–0.61, p < 0.0001, respectively). In the validation cohort from two institutes (n = 57), similar significant improvements in PFS and OS were confirmed for patients with NLR-low (p = 0.0344 and p = 0.0233, respectively) and CRP-low groups (p < 0.0001 and p = 0.0001, respectively). Low levels of NLR and CRP at baseline were significantly associated with improved prognosis in patients treated with bevacizumab plus paclitaxel.
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Affiliation(s)
- Yoshimasa Miyagawa
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Ayako Yanai
- Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo 660-8511, Japan
| | - Takehiro Yanagawa
- Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo 660-8511, Japan
| | - Junichi Inatome
- Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo 660-8511, Japan
| | - Chiyomi Egawa
- Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo 660-8511, Japan
| | - Arisa Nishimukai
- Department of Breast Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Kaori Takamoto
- Department of Breast Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Takashi Morimoto
- Department of Breast Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Yuichiro Kikawa
- Department of Breast Surgery, Kobe City Medical Center General Hospital, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Hirofumi Suwa
- Department of Breast Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo 660-8550, Japan
| | - Tomoe Taji
- Department of Breast Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo 660-8550, Japan
| | - Ai Yamaguchi
- Department of Breast Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo 660-8550, Japan
| | - Yuki Okada
- Department of Breast Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo 660-8550, Japan
| | - Atsushi Sata
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Reiko Fukui
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Ayako Bun
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiromi Ozawa
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Tomoko Higuchi
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Yukie Fujimoto
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Michiko Imamura
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Yasuo Miyoshi
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
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