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Dowsing B, Dehbi HM, Chung R, Pedra J, Worn O, Artico J, Schmid P, Roylance R, Kellman P, Moon JC, Crake T, Westwood M, Ghosh A, Andres MS, Nazir MS, Lyon AR, Chen D, Walker M, Manisty CH. HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction. BMJ Open 2025; 15:e091917. [PMID: 39909533 PMCID: PMC11800297 DOI: 10.1136/bmjopen-2024-091917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 01/20/2025] [Indexed: 02/07/2025] Open
Abstract
INTRODUCTION A quarter of breast cancers show human epidermal growth factor-2 (HER2) overexpression, where targeted therapy dramatically improves survival. However, cancer therapy-related cardiac dysfunction (CTRCD) occurs in up to 15% of patients. With the interruption of HER2 therapy, if necessary, and the initiation of heart failure therapy (HFT), HER2 CTRCD recovers in over 80% of cases. The need to continue HFT in 'recovered' HER2 CTRCD following completion of HER2 therapy is unclear and there are potential significant impacts on patient's quality of life (QoL). The Randomised Controlled Trial for the Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction (HER-SAFE) aims to evaluate whether HFT can be safely withdrawn in non-high cardiovascular (CV) risk patients with 'recovered' HER2 CTRCD. METHODS AND ANALYSIS This is a multicentre, open-label randomised controlled trial investigating whether withdrawal of HFT is non-inferior to continuation in non-high CV risk, breast cancer survivors with recovered HER2 CTRCD after cancer treatment completion. The primary endpoint is the incidence of guideline-defined cardiac dysfunction or clinical heart failure. Secondary endpoints include changes in cardiac blood biomarkers, cardiovascular magnetic resonance (CMR)-derived strain and tissue mapping and heart failure symptom questionnaires. The study will recruit 90 participants who will undergo serial clinical assessment over 12 months with advanced cardiovascular imaging (CMR scans with automated analysis at baseline, 6 and 12 months), cardiac biomarker measurement (six time points over 12 months), plus complete heart failure QoL and medication disutility questionnaires. This is the first multicentre study to address this significant clinical issue. ETHICS AND DISSEMINATION This study was approved by the research ethics committee (London-London Bridge, 23/LO/0152). The results will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER NCT05880160.
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Affiliation(s)
- Benjamin Dowsing
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | | | - Robin Chung
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
- Whittington Health NHS Trust, London, UK
| | - Joanna Pedra
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Orla Worn
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Jessica Artico
- Institute of Cardiovascular Science, University College London, London, UK
- Imperial College Healthcare NHS Trust Cardiology Service, London, UK
| | - Peter Schmid
- Queen Mary University of London, London, UK
- Barts Health NHS Trust, London, UK
| | | | - Peter Kellman
- National Heart Lung and Blood Institute, Bethesda, Maryland, USA
| | - James C Moon
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Tom Crake
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Mark Westwood
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Arjun Ghosh
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Maria Sol Andres
- Cardio-Oncology Centre of Excellence, Royal Brompton Hospital, London, UK
| | - Muhummad Sohaib Nazir
- King's College London School of Biomedical Engineering & Imaging Sciences, London, UK
- Cardio-Oncology Centre of Excellence, Royal Brompton and Harefield Hospitals, London, UK
| | - Alexander R Lyon
- Cardio-Oncology Centre of Excellence, Royal Brompton Hospital, London, UK
| | - Daniel Chen
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
| | - Malcolm Walker
- Institute of Cardiovascular Science, University College London, London, UK
| | - Charlotte H Manisty
- Institute of Cardiovascular Science, University College London, London, UK
- Saint Bartholomew's Hospital Barts Heart Centre, London, UK
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Baugh AG, Gonzalez E, Narumi VH, Kreger J, Liu Y, Rafie C, Castanon S, Jang J, Kagohara LT, Anastasiadou DP, Leatherman J, Armstrong T, Chan I, Karagiannis GS, Jaffee EM, MacLean A, Torres ETR. A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer. Clin Exp Metastasis 2024; 41:733-746. [PMID: 38717519 PMCID: PMC11499368 DOI: 10.1007/s10585-024-10289-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/21/2024] [Indexed: 07/15/2024]
Abstract
Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.
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Affiliation(s)
- Aaron G Baugh
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Edgar Gonzalez
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Valerie H Narumi
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jesse Kreger
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Yingtong Liu
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Christine Rafie
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sofi Castanon
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Julie Jang
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA
| | - Luciane T Kagohara
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Dimitra P Anastasiadou
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - James Leatherman
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Todd Armstrong
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Isaac Chan
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - George S Karagiannis
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Elizabeth M Jaffee
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Adam MacLean
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Evanthia T Roussos Torres
- Department of Medicine, Division of Medical Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave, Suite 6412, Los Angeles, CA, 90033, USA.
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Baugh AG, Gonzalez E, Narumi VH, Kreger J, Liu Y, Rafie C, Castanon S, Jang J, Kagohara LT, Anastasiadou DP, Leatherman J, Armstrong TD, Chan I, Karagiannis GS, Jaffee EM, MacLean A, Roussos Torres ET. Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2 + breast cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.25.577282. [PMID: 38352476 PMCID: PMC10862766 DOI: 10.1101/2024.01.25.577282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/19/2024]
Abstract
Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.
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Affiliation(s)
- Aaron G. Baugh
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Edgar Gonzalez
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Valerie H. Narumi
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jesse Kreger
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Yingtong Liu
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Christine Rafie
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sofi Castanon
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Julie Jang
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Luciane T. Kagohara
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Dimitra P. Anastasiadou
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Tumor Microenvironment & Metastasis Program, Montefiore-Einstein Cancer Center, Bronx, NY, USA
| | - James Leatherman
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Todd D. Armstrong
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Isaac Chan
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - George S. Karagiannis
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Tumor Microenvironment & Metastasis Program, Montefiore-Einstein Cancer Center, Bronx, NY, USA
- Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA
- Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Elizabeth M. Jaffee
- Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Adam MacLean
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
| | - Evanthia T. Roussos Torres
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Alhuseinalkhudhur A, Lindman H, Liss P, Sundin T, Frejd FY, Hartman J, Iyer V, Feldwisch J, Lubberink M, Rönnlund C, Tolmachev V, Velikyan I, Sörensen J. Human Epidermal Growth Factor Receptor 2-Targeting [ 68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer. J Nucl Med 2023; 64:1364-1370. [PMID: 37442602 PMCID: PMC10478820 DOI: 10.2967/jnumed.122.265364] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/10/2023] [Indexed: 07/15/2023] Open
Abstract
Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.
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Affiliation(s)
- Ali Alhuseinalkhudhur
- Division of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden;
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Henrik Lindman
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Per Liss
- Division of Radiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Tora Sundin
- Clinical Research and Development Unit, Uppsala University Hospital, Uppsala, Sweden
| | - Fredrik Y Frejd
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
- Affibody AB, Solna, Sweden
| | - Johan Hartman
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden; and
| | - Victor Iyer
- Division of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Mark Lubberink
- Division of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
- Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden
| | - Caroline Rönnlund
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden; and
| | - Vladimir Tolmachev
- Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden
| | - Irina Velikyan
- Division of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jens Sörensen
- Division of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Rakha EA, Tan PH, Quinn C, Provenzano E, Shaaban AM, Deb R, Callagy G, Starczynski J, Lee AHS, Ellis IO, Pinder SE. UK recommendations for HER2 assessment in breast cancer: an update. J Clin Pathol 2023; 76:217-227. [PMID: 36564170 DOI: 10.1136/jcp-2022-208632] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/09/2022] [Indexed: 12/25/2022]
Abstract
The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 and HER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.
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Affiliation(s)
- Emad A Rakha
- Cellular Patthology Department, School of Medicine, University of Nottingham, Nottingham, UK
| | | | - Cecily Quinn
- Department of Histopathology, St Vincent's University Hospital, Elm Park and and UCD School of Medicine, Dublin, Ireland
| | - Elena Provenzano
- Department of Histopathology, Addenbrookes Hospital, Cambridge, UK
| | - Abeer M Shaaban
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trusts and Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Rahul Deb
- Cellular Pathology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK
| | - Grace Callagy
- Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, University of Galway, Galway, Ireland
| | - Jane Starczynski
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trusts, Birmingham, UK
| | - Andrew H S Lee
- Cellular Pathology Department, City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Ian O Ellis
- Cellular Patthology Department, School of Medicine, University of Nottingham, Nottingham, UK
| | - Sarah E Pinder
- School of Cancer & Pharmaceutical Sciences, Kings College London, London, UK
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Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer. Proc Natl Acad Sci U S A 2022; 119:2112491119. [PMID: 34969858 PMCID: PMC8740706 DOI: 10.1073/pnas.2112491119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2021] [Indexed: 12/27/2022] Open
Abstract
Brain metastases are among the most severe complications of systemic breast cancer, and overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer cells increases the incidence of brain metastases in patients. In this study, we engineered the human-derived, tumor cell tropic neural stem cells LM-NSC008 (LM008) to continuously secrete antibodies against HER2. These anti-HER2 antibodies impaired tumor cell proliferation by inhibiting the PI3K-Akt signaling pathway in HER2+ breast cancer cells in vitro. Importantly, our results demonstrate that the therapeutic combinatorial regimen consisting of LM-NSC008 anti-HER2 antibody-secreting cells and the HER2 kinase inhibitor tucatinib provide therapeutic benefit and prolong survival in preclinical models of HER2+ breast cancer brain metastases. Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood–brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.
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Kute T, Stehle JR, Ornelles D, Walker N, Delbono O, Vaughn JP. Understanding key assay parameters that affect measurements of trastuzumab-mediated ADCC against Her2 positive breast cancer cells. Oncoimmunology 2021; 1:810-821. [PMID: 23162748 PMCID: PMC3489736 DOI: 10.4161/onci.20447] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Use of the antibody trastuzumab to kill HER2+ breast cancer cells is an attractive therapy because of its specificity and minimal adverse effects. However, a large fraction of HER2+ positive patients are or will become resistant to this treatment. No other markers are used to determine sensitivity to trastuzumab other than HER2 status.Using the xCELLigence platform and flow cytometry, we have compared the ability of mononuclear cells (MNCs) from normal and breast cancer patients to kill different breast cancer cell lines in the presence (i.e., ADCC) or absence of trastuzumab. Image analysis and cell separation procedures were used to determine the differential contribution of immune cell subsets to ADCC activity. The assay demonstrated that ADCC activity is dependent on the presence of trastuzumab, the level of HER2 expression on the target, and the ratio of MNCs to tumor cells. There is a wide range of ADCC activity among normal individuals and breast cancer patients for high and low HER2-expressing tumor targets. Fresh MNCs display higher ADCC levels compared with cryopreserved cells. Natural killer cells display the highest ADCC followed by monocytes. T cells and B cells were ineffective in killing. A major mechanism of killing of tumor cells involves insertion of granzyme B and caspase enzymes via the antibody attached MNCs.
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Affiliation(s)
- Timothy Kute
- Pathology; Wake Forest University School of Medicine; Winston-Salem, NC USA
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Saito K, Kaneko R, Kamio T, Kamiyama E, Muto R, Sugihara M. [Pharmacological and clinical study results of trastuzumab deruxtecan (T-DXd, ENHERTU ®)]. Nihon Yakurigaku Zasshi 2021; 156:47-51. [PMID: 33390481 DOI: 10.1254/fpj.20076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Antibody-drug conjugates (ADCs) combine the specific antibody and cytotoxic agent by a linker and represent a promising drug class with a wider therapeutic window than conventional chemotherapeutic agents by substantiating efficient and specific drug delivery to antigen-expressing tumor cells. However, there are rooms for improvement in terms of efficacy, safety, physicochemical property; therefore, the development of promising ADC drugs across multiple indications are eagerly awaited. In 2015, Daiichi Sankyo initiated the first-in-human study of HER2 ADC, trastuzumab deruxtecan (T-DXd, ENHERTU®) which possesses DNA topoisomerase I inhibitor, exatecan derivative and proprietary linker, in Japan. Based on the provocative results in phase 1 study, the global development program has been accelerated to show the high and durable efficacy in patients with HER2 positive breast cancer pretreated with trastuzumab emtansine. As a result, T-DXd was approved based on single arm phase 2 study in the US (Dec 2019) and Japan (March 2020) by leveraging the breakthrough designation and conditional early approval system, respectively, at the first time for the HER2 positive breast cancer. In addition, T-DXd was recently approved in gastric cancer through Sakigake designation in Japan based on a randomized phase 2 study. T-DXd is also being developed in the earlier lines or other indications where no anti-HER2 therapies were approved to date. Combination studies with other agents, such as immune checkpoint inhibitors are underway. In the near future, we hope that more patients worldwide can enjoy the therapeutic benefits of T-DXd through our continuous efforts to expand its indications.
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9
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Rodriguez-Mateos P, Azevedo NF, Almeida C, Pamme N. FISH and chips: a review of microfluidic platforms for FISH analysis. Med Microbiol Immunol 2020; 209:373-391. [PMID: 31965296 PMCID: PMC7248050 DOI: 10.1007/s00430-019-00654-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022]
Abstract
Fluorescence in situ hybridization (FISH) allows visualization of specific nucleic acid sequences within an intact cell or a tissue section. It is based on molecular recognition between a fluorescently labeled probe that penetrates the cell membrane of a fixed but intact sample and hybridizes to a nucleic acid sequence of interest within the cell, rendering a measurable signal. FISH has been applied to, for example, gene mapping, diagnosis of chromosomal aberrations and identification of pathogens in complex samples as well as detailed studies of cellular structure and function. However, FISH protocols are complex, they comprise of many fixation, incubation and washing steps involving a range of solvents and temperatures and are, thus, generally time consuming and labor intensive. The complexity of the process, the relatively high-priced fluorescent probes and the fairly high-end microscopy needed for readout render the whole process costly and have limited wider uptake of this powerful technique. In recent years, there have been attempts to transfer FISH assay protocols onto microfluidic lab-on-a-chip platforms, which reduces the required amount of sample and reagents, shortens incubation times and, thus, time to complete the protocol, and finally has the potential for automating the process. Here, we review the wide variety of approaches for lab-on-chip-based FISH that have been demonstrated at proof-of-concept stage, ranging from FISH analysis of immobilized cell layers, and cells trapped in arrays, to FISH on tissue slices. Some researchers have aimed to develop simple devices that interface with existing equipment and workflows, whilst others have aimed to integrate the entire FISH protocol into a fully autonomous FISH on-chip system. Whilst the technical possibilities for FISH on-chip are clearly demonstrated, only a small number of approaches have so far been converted into off-the-shelf products for wider use beyond the research laboratory.
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Affiliation(s)
- Pablo Rodriguez-Mateos
- Department of Chemistry and Biochemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK
| | - Nuno Filipe Azevedo
- LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Department of Chemical Engineering, Faculty of Engineering of University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal
- Biomode SA, Av. Mestre José Veiga, 4715-330, Braga, Portugal
| | - Carina Almeida
- Biomode SA, Av. Mestre José Veiga, 4715-330, Braga, Portugal
- INIAV, I.P.-National Institute for Agricultural and Veterinary Research, Rua dos Lagidos, Lugar da Madalena, Vairão, 4485-655, Vila Do Conde, Portugal
- CEB-Centre of Biological Engineering, University of Minho, 4710-057, Braga, Portugal
| | - Nicole Pamme
- Department of Chemistry and Biochemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
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10
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Keung MY, Wu Y, Badar F, Vadgama JV. Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status. J Clin Med 2020; 9:jcm9040940. [PMID: 32235451 PMCID: PMC7231148 DOI: 10.3390/jcm9040940] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven to be beneficial to patients with metastatic breast cancer with BRCA1/2 (BReast CAncer type 1 and type 2 genes) mutations. However, certain PARPi in pre-clinical studies have been shown to inhibit cell growth and promote the death of breast cancer cells lacking mutations in BRCA1/2. Here, we examined the inhibitory potency of 13 different PARPi in 12 breast cancer cell lines with and without BRCA-mutations using cell viability assays. The results showed that 5 of the 8 triple-negative breast cancer (TNBC) cell lines were susceptible to PARPi regardless of the BRCA-status. The estrogen receptor (ER) negative/ human epidermal growth factor receptor 2 (HER2) positive (ER-/HER2+) cells, SKBR3 and JIMT1, showed high sensitivity to Talazoparib. Especially JIMT1, which is known to be resistant to trastuzumab, was responsive to Talazoparib at 0.002 µM. Niraparib, Olaparib, and Rucaparib also demonstrated effective inhibitory potency in both advanced TNBC and ER-/HER2+ cells with and without BRCA-mutations. In contrast, a BRCA-mutant TNBC line, HCC1937, was less sensitive to Talazoparib, Niraparib, Rucaparib, and not responsive to Olaparib. Other PARPi such as UPF1069, NU1025, AZD2461, and PJ34HCl also showed potent inhibitory activity in specific breast cancer cells. Our data suggest that the benefit of PARPi therapy in breast cancer is beyond the BRCA-mutations, and equally effective on metastatic TNBC and ER-/HER2+ breast cancers.
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Affiliation(s)
- Man Yee Keung
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (M.Y.K.); (F.B.)
| | - Yanyuan Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (M.Y.K.); (F.B.)
- David Geffen UCLA School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
- Correspondence: (Y.W.); (J.V.V.)
| | - Francesca Badar
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (M.Y.K.); (F.B.)
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (M.Y.K.); (F.B.)
- David Geffen UCLA School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
- Correspondence: (Y.W.); (J.V.V.)
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11
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Kikuchi R, Shah NP, Dent SF. Strategies to Prevent Cardiovascular Toxicity in Breast Cancer: Is It Ready for Primetime? J Clin Med 2020; 9:E896. [PMID: 32218132 PMCID: PMC7230166 DOI: 10.3390/jcm9040896] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/16/2020] [Accepted: 03/20/2020] [Indexed: 11/16/2022] Open
Abstract
Cardio-oncology is an emerging field tasked with identifying and treating cancer therapy related cardiac dysfunction (e.g., cytotoxic agents, immunotherapies, radiation, and hormone therapies) and optimizing the cardiovascular health of cancer patients exposed to these agents. Novel cancer therapies have led to significant improvements in clinical outcomes for breast cancer patients. In this article, we review the current literature on assessing cardiovascular risk of breast cancer therapies and discuss strategies (including pharmacological and lifestyle interventions) to prevent cardiovascular toxicity.
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Affiliation(s)
- Robin Kikuchi
- Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27710, USA;
| | - Nishant P. Shah
- Division of Cardiology, Duke Heart Center, Duke University, Durham, NC 27710, USA;
| | - Susan F. Dent
- Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27710, USA;
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12
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Berko YA, Akala EO. Computer Optimization of Stealth Biodegradable Polymeric Dual-loaded Nanoparticles for Cancer Therapy Using Central Composite Face-centered Design. Pharm Nanotechnol 2020; 8:108-132. [PMID: 32091350 DOI: 10.2174/2211738508666200224110410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/03/2020] [Accepted: 02/04/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Combination chemotherapy capable of overcoming cancer drug resistance can be facilitated by nanotechnology. OBJECTIVE Synthesis, characterization, statistical experimental design, analysis and optimization of stealth pH-sensitive polymeric nanoparticles suitable as a platform for simultaneous delivery of paclitaxel and 17-AAG in breast cancer therapy were investigated. METHODS An acetal crosslinker and a poly(ɛ)caprolactone macromonomer were synthesized and characterized. The statistical experimental design used was the response surface method (RSM). We used the central composite face-centered design (CCF) in three independent factors and seventeen runs. Nanoparticles were fabricated by dispersion polymerization techniques. Response variables evaluated were: particle size, drug loading, encapsulation efficiency, and in vitro availability. RESULTS Scanning electron micrographs showed the formation of spherical nanoparticles. Computer software was used for the analysis of variance with a 95% confidence level and Q2 (goodness of prediction) to select an appropriate model for each of the response variables. Each term in each of the models was tested for the significance of the regression coefficients. The computer software optimizer was used for optimization to select factor combination to minimize particle size, time (h) for maximum release of paclitaxel and 17-AAG, to maximize paclitaxel and 17-AAG loading efficiency and to maximize paclitaxel and 17-AAG encapsulation efficiency. CONCLUSION The optimization was successful, as shown by the validation data which lie within the confidence intervals of predicted values of the response variables. The selected factor combination is suitable for the in vivo evaluation of the nanoparticles loaded with paclitaxel and 17-AAG.
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Affiliation(s)
- Yvonne A Berko
- Center for Drug Research and Development, Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, 2300 4th Street, NW, Washington, DC 20059, United States
| | - Emmanuel O Akala
- Center for Drug Research and Development, Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, 2300 4th Street, NW, Washington, DC 20059, United States
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13
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MET targeting: time for a rematch. Oncogene 2020; 39:2845-2862. [PMID: 32034310 DOI: 10.1038/s41388-020-1193-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/16/2020] [Accepted: 01/24/2020] [Indexed: 12/21/2022]
Abstract
MET, the receptor tyrosine kinase (RTK) for hepatocyte growth factor, is a proto-oncogene involved in embryonic development and throughout life in homeostasis and tissue regeneration. Deregulation of MET signaling has been reported in numerous malignancies, prompting great interest in MET targeting for cancer therapy. The present review offers a summary of the biology of MET and its known functions in normal physiology and carcinogenesis, followed by an overview of the most relevant MET-targeting strategies and corresponding clinical trials, highlighting both past setbacks and promising future prospects. By placing their efforts on a more precise stratification strategy through the genetic analysis of tumors, modern trials such as the NCI-MATCH trial could revive the past enthusiasm for MET-targeted therapy.
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14
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González García J, Gutiérrez Nicolás F, Ramos Díaz R, Nazco Casariego GJ, Viña Romero MM, Llabres Martinez M, Llanos Muñoz M, Batista López JN, Jiménez Sosa A, Ceballos Lenza I, Cruz Jurado J. Pharmacokinetics of Trastuzumab After Subcutaneous and Intravenous Administration in Obese Patients. Ann Pharmacother 2020; 54:775-779. [PMID: 31971005 DOI: 10.1177/1060028020902318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient's body weight dose) on the initial minimum plasma concentration (Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight-adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.
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Affiliation(s)
| | | | - Ruth Ramos Díaz
- Fundación Canaria para la Investigación Sanitaria (FUNCANIS), Santa Cruz de Tenerife, La Laguna, Spain
| | | | | | | | - Marta Llanos Muñoz
- Complejo Hospitalario Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, Spain
| | | | - Alejandro Jiménez Sosa
- Complejo Hospitalario Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, Spain
| | - Isaac Ceballos Lenza
- Complejo Hospitalario Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, Spain
| | - Josefina Cruz Jurado
- Complejo Hospitalario Universitario de Canarias, Santa Cruz de Tenerife, La Laguna, Spain
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15
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Rezaie E, Amani J, Bidmeshki Pour A, Mahmoodzadeh Hosseini H. A new scfv-based recombinant immunotoxin against EPHA2-overexpressing breast cancer cells; High in vitro anti-cancer potency. Eur J Pharmacol 2020; 870:172912. [PMID: 31926992 DOI: 10.1016/j.ejphar.2020.172912] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 12/12/2019] [Accepted: 01/07/2020] [Indexed: 11/25/2022]
Abstract
Immunotoxin therapy is one of the immunotherapy strategies providing a new, effective and high potency treatment against various cancers. Breast cancer is the most common cancer among women in many countries. The EPH receptors are a large part of tyrosine kinase receptors family and play an effective role in tumor development and angiogenesis. Among EPH receptors, EPHA2 is more commonly well-known and widely expressed in many cancers like breast cancer. In this study, we evaluated the specification of a designed immunotoxin formed by EPHA2-specific scfv linked with PE38KDEL on EPHA2-overexpressing breast cancer cell line. This new scfv-based recombinant immunotoxin was studied in terms of features such as binding potency, cytotoxicity effects, apoptosis induction ability, and internalization. The flow cytometry results showed that the immunotoxin can significantly (approximately 99%) bind to EPHA2-overexpressing breast cancer cell line (MDA-MB-231) in a low concentration (2.5 ng/ul) while cannot significantly bind to the normal cell line (HEK-293) or even EPHA2-very low expressing cell line (MCF-7). Using the MTT assay and Annexin V/Propidium iodide (PI) double staining method by flow cytometry, we observed significant killing and apoptosis induction of the MDA-MB-231 cells at different concentrations. Immunotoxin tracking by confocal microscopy at 2 h and 6 h revealed a massive presence of immunotoxin in the cytoplasm. Finally, given the in vitro results, it seems that this immunotoxin is competent enough to serve as a good candidate for in vivo studies to further explore the possibility of breast cancer treatment.
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Affiliation(s)
- Ehsan Rezaie
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran; Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Science, Tehran, Iran.
| | - Jafar Amani
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Ali Bidmeshki Pour
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran.
| | - Hamideh Mahmoodzadeh Hosseini
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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16
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Laengle J, Kabiljo J, Hunter L, Homola J, Prodinger S, Egger G, Bergmann M. Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis. J Immunother Cancer 2020; 8:jitc-2019-000195. [PMID: 31940587 PMCID: PMC7057438 DOI: 10.1136/jitc-2019-000195] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2019] [Indexed: 01/02/2023] Open
Abstract
Background The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized. Methods We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach. Results VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells. Conclusions HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.
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Affiliation(s)
- Johannes Laengle
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.,Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
| | - Julijan Kabiljo
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Leah Hunter
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Jakob Homola
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Sophie Prodinger
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Gerda Egger
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Michael Bergmann
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria .,Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
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17
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Böckelmann LC, Schumacher U. Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors? Expert Opin Ther Targets 2019; 23:1005-1014. [DOI: 10.1080/14728222.2019.1702974] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Lukas Clemens Böckelmann
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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18
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Warchal SJ, Dawson JC, Shepherd E, Munro AF, Hughes RE, Makda A, Carragher NO. High content phenotypic screening identifies serotonin receptor modulators with selective activity upon breast cancer cell cycle and cytokine signaling pathways. Bioorg Med Chem 2019; 28:115209. [PMID: 31757681 PMCID: PMC6961118 DOI: 10.1016/j.bmc.2019.115209] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023]
Abstract
Heterogeneity in disease mechanisms between genetically distinct patients contributes to high attrition rates in late stage clinical drug development. New personalized medicine strategies aim to identify predictive biomarkers which stratify patients most likely to respond to a particular therapy. However, for complex multifactorial diseases not characterized by a single genetic driver, empirical approaches to identifying predictive biomarkers and the most promising therapies for personalized medicine are required. In vitro pharmacogenomics seeks to correlate in vitro drug sensitivity testing across panels of genetically distinct cell models with genomic, gene expression or proteomic data to identify predictive biomarkers of drug response. However, the vast majority of in vitro pharmacogenomic studies performed to date are limited to dose-response screening upon a single viability assay endpoint. In this article we describe the application of multiparametric high content phenotypic screening and the theta comparative cell scoring method to quantify and rank compound hits, screened at a single concentration, which induce a broad variety of divergent phenotypic responses between distinct breast cancer cell lines. High content screening followed by transcriptomic pathway analysis identified serotonin receptor modulators which display selective activity upon breast cancer cell cycle and cytokine signaling pathways correlating with inhibition of cell growth and survival. These methods describe a new evidence-led approach to rapidly identify compounds which display distinct response between different cell types. The results presented also warrant further investigation of the selective activity of serotonin receptor modulators upon breast cancer cell growth and survival as a potential drug repurposing opportunity.
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Affiliation(s)
- Scott J Warchal
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom
| | - John C Dawson
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom.
| | - Emelie Shepherd
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom
| | - Alison F Munro
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom
| | - Rebecca E Hughes
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom
| | - Ashraff Makda
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom
| | - Neil O Carragher
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom.
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19
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van Vloten JP, Klafuric EM, Karimi K, McFadden G, Petrik JJ, Wootton SK, Bridle BW. Quantifying Antibody Responses Induced by Antigen-Agnostic Immunotherapies. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 14:189-196. [PMID: 31388514 PMCID: PMC6677899 DOI: 10.1016/j.omtm.2019.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/29/2019] [Indexed: 12/30/2022]
Abstract
As the development and clinical application of cancer immunotherapies continue to expand, so does the need for novel methods to dissect their mechanisms of action. Antibodies are important effector molecules in cancer therapies due to their potential to bind directly to surface-expressed antigens and facilitate Fc receptor-mediated uptake of antigens by antigen-presenting cells. Quantifying antibodies that are specific for defined antigens is straightforward. However, we describe herein a preclinical method to evaluate tumor-associated and virus-specific antibody responses to antigen-agnostic immunotherapies. This method uses autologous tumor cells as reservoirs of bulk tumor antigens, which can be bound by antibodies from the serum or plasma of tumor-bearing mice. These antibodies can then be detected and quantified using isotype-specific secondary antibodies conjugated to a fluorochrome. Alternatively, virus-infected cells can be used as a source of viral antigens. This method will enable researchers to assess antibody responses following immunotherapies without requiring pre-defined antigens. Alternatively, total virus-specific antibody responses could be studied as an alternative to more limited virus-neutralizing antibody assays. Therefore, this method can facilitate studying the role of humoral responses in the context of immunotherapies, including those that rely on the use of viral vectors.
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Affiliation(s)
- Jacob P van Vloten
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Elaine M Klafuric
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Khalil Karimi
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Grant McFadden
- The Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - James J Petrik
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Sarah K Wootton
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Byram W Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
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Pinyol R, Montal R, Bassaganyas L, Sia D, Takayama T, Chau GY, Mazzaferro V, Roayaie S, Lee HC, Kokudo N, Zhang Z, Torrecilla S, Moeini A, Rodriguez-Carunchio L, Gane E, Verslype C, Croitoru AE, Cillo U, de la Mata M, Lupo L, Strasser S, Park JW, Camps J, Solé M, Thung SN, Villanueva A, Pena C, Meinhardt G, Bruix J, Llovet JM. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut 2019; 68:1065-1075. [PMID: 30108162 PMCID: PMC6580745 DOI: 10.1136/gutjnl-2018-316408] [Citation(s) in RCA: 234] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/16/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER NCT00692770.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Angiogenesis Inhibitors/therapeutic use
- Biopsy, Needle
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Chemotherapy, Adjuvant
- Disease-Free Survival
- Female
- Humans
- Immunohistochemistry
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Male
- Middle Aged
- Molecular Targeted Therapy/methods
- Neoplasm Invasiveness/pathology
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplasm Staging
- Predictive Value of Tests
- Prognosis
- Sorafenib/therapeutic use
- Survival Analysis
- Tissue Embedding
- Treatment Outcome
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Affiliation(s)
- Roser Pinyol
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Robert Montal
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Laia Bassaganyas
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Daniela Sia
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Gar-Yang Chau
- Department of surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Vincenzo Mazzaferro
- Hepatology and Liver Transplantation Unit, Department of Surgery, University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sasan Roayaie
- Liver Cancer Program, White Plains Hospital, Montefiore Health, New York City, New York, USA
| | - Han Chu Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Zhongyang Zhang
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Sara Torrecilla
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Agrin Moeini
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Leonardo Rodriguez-Carunchio
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Chris Verslype
- Department of Hepatology, University Hospital Leuven, Leuven, Belgium
| | | | - Umberto Cillo
- Unità Operativa di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera Università di Padova, Padova, Italy
| | - Manuel de la Mata
- Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain
| | - Luigi Lupo
- Sezione Chirurgia Generale e Trapianti di Fegato, Policlinico di Bari, Bari, Italy
| | - Simone Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital-University of Sydney, Sydney, New South Wales, Australia
| | - Joong-Won Park
- Department of Cancer Control and Population Health, National Cancer Center, Goyang, South Korea
| | - Jordi Camps
- Gastrointestinal and Pancreatic Oncology Group, IDIBAPS-Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Manel Solé
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Swan N Thung
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Carol Pena
- Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
| | | | - Jordi Bruix
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Josep M Llovet
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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21
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Eguchi A, Nakakido M, Nagatoishi S, Kuroda D, Tsumoto K, Nagamune T, Kawahara M. An epitope‐directed antibody affinity maturation system utilizing mammalian cell survival as readout. Biotechnol Bioeng 2019; 116:1742-1751. [DOI: 10.1002/bit.26965] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/15/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Akihiro Eguchi
- Department of Chemistry and BiotechnologyGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
| | - Makoto Nakakido
- Department of BioengineeringGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
| | - Satoru Nagatoishi
- Department of BioengineeringGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
- The Institute of Medical Science, The University of Tokyo, Minato‐kuTokyo Japan
| | - Daisuke Kuroda
- Department of BioengineeringGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
| | - Kouhei Tsumoto
- Department of BioengineeringGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
- The Institute of Medical Science, The University of Tokyo, Minato‐kuTokyo Japan
| | - Teruyuki Nagamune
- Department of Chemistry and BiotechnologyGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
| | - Masahiro Kawahara
- Department of Chemistry and BiotechnologyGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
- Department of BioengineeringGraduate School of Engineering, The University of Tokyo, Bunkyo‐kuTokyo Japan
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22
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Jarczewska M, Trojan A, Gągała M, Malinowska E. Studies on the Affinity‐based Biosensors for Electrochemical Detection of HER2 Cancer Biomarker. ELECTROANAL 2019. [DOI: 10.1002/elan.201900041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Marta Jarczewska
- The Chair of Medical BiotechnologyFaculty of ChemistryWarsaw University of Technology Noakowskiego 3 00-664 Warsaw Poland
| | - Anita Trojan
- The Chair of Medical BiotechnologyFaculty of ChemistryWarsaw University of Technology Noakowskiego 3 00-664 Warsaw Poland
| | - Małgorzata Gągała
- The Chair of Medical BiotechnologyFaculty of ChemistryWarsaw University of Technology Noakowskiego 3 00-664 Warsaw Poland
| | - Elżbieta Malinowska
- The Chair of Medical BiotechnologyFaculty of ChemistryWarsaw University of Technology Noakowskiego 3 00-664 Warsaw Poland
- Centre for Advanced Materials and Technologies CEZAMAT Poleczki 19 02-822 Warsaw Poland
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23
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Sangsuwan R, Tachachartvanich P, Francis MB. Cytosolic Delivery of Proteins Using Amphiphilic Polymers with 2-Pyridinecarboxaldehyde Groups for Site-Selective Attachment. J Am Chem Soc 2019; 141:2376-2383. [DOI: 10.1021/jacs.8b10947] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
| | | | - Matthew B. Francis
- Materials Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720, United States
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24
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Ghasabi M, Mansoori B, Mohammadi A, Duijf PH, Shomali N, Shirafkan N, Mokhtarzadeh A, Baradaran B. MicroRNAs in cancer drug resistance: Basic evidence and clinical applications. J Cell Physiol 2018; 234:2152-2168. [PMID: 30146724 DOI: 10.1002/jcp.26810] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/30/2018] [Indexed: 12/19/2022]
Abstract
Development of drug resistance has considerably limited the efficacy of cancer treatments, including chemotherapy and targeted therapies. Hence, understanding the molecular mechanisms underpinning the innate or the acquired resistance to these therapies is critical to improve drug efficiency and clinical outcomes. Several studies have implicated microRNAs (miRNA) in this process. MiRNAs repress gene expression by specific binding to complementary sequences in the 3' region of target messenger RNAs (mRNAs), followed by target mRNA degradation or blocked translation. By targeting molecules specific to a particular pathway within tumor cells, the new generation of cancer treatment strategies has shown significant advantages over conventional chemotherapy. However, the long-term efficacy of targeted therapies often remains poor, because tumor cells develop resistance to such therapeutics. Targeted therapies often involve monoclonal antibodies (mAbs), such as those blocking the ErB/HER tyrosine kinases, epidermal growth factor receptor (cetuximab) and HER2 (trastuzumab), and those inhibiting vascular endothelial growth factor receptor signaling (e.g., bevacizumab). Even though these are among the most used agents in tumor medicine, clinical response to these drugs is reduced due to the emergence of drug resistance as a result of toxic effects in the tumor microenvironment. Research on different types of human cancers has revealed that aberrant expression of miRNAs promotes resistance to the aforementioned drugs. In this study, we review the mechanisms of tumor cell resistance to mAb therapies and the role of miRNAs therein. Emerging treatment strategies combine therapies using innovative miRNA mimics or antagonizers with conventional approaches to maximize outcomes of patients with cancer.
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Affiliation(s)
- Mehri Ghasabi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pascal Hg Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Naghmeh Shirafkan
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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25
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Stéen EJL, Edem PE, Nørregaard K, Jørgensen JT, Shalgunov V, Kjaer A, Herth MM. Pretargeting in nuclear imaging and radionuclide therapy: Improving efficacy of theranostics and nanomedicines. Biomaterials 2018; 179:209-245. [PMID: 30007471 DOI: 10.1016/j.biomaterials.2018.06.021] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 06/13/2018] [Accepted: 06/14/2018] [Indexed: 01/18/2023]
Abstract
Pretargeted nuclear imaging and radiotherapy have recently attracted increasing attention for diagnosis and treatment of cancer with nanomedicines. This is because it conceptually offers better imaging contrast and therapeutic efficiency while reducing the dose to radiosensitive tissues compared to conventional strategies. In conventional imaging and radiotherapy, a directly radiolabeled nano-sized vector is administered and allowed to accumulate in the tumor, typically on a timescale of several days. In contrast, pretargeting is based on a two-step approach. First, a tumor-accumulating vector carrying a tag is administered followed by injection of a fast clearing radiolabeled agent that rapidly recognizes the tag of the tumor-bound vector in vivo. Therefore, pretargeting circumvents the use of long-lived radionuclides that is a necessity for sufficient tumor accumulation and target-to-background ratios using conventional approaches. In this review, we give an overview of recent advances in pretargeted imaging strategies. We will critically reflect on the advantages and disadvantages of current state-of-the-art conventional imaging approaches and compare them to pretargeted strategies. We will discuss the pretargeted imaging concept and the involved chemistry. Finally, we will discuss the steps forward in respect to clinical translation, and how pretargeted strategies could be applied to improve state-of-the-art radiotherapeutic approaches.
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Affiliation(s)
- E Johanna L Stéen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Patricia E Edem
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2100 Copenhagen, Denmark
| | - Kamilla Nørregaard
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2100 Copenhagen, Denmark
| | - Jesper T Jørgensen
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2100 Copenhagen, Denmark
| | - Vladimir Shalgunov
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2100 Copenhagen, Denmark
| | - Matthias M Herth
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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26
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Therapeutic Antibodies in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 917:95-120. [PMID: 27236554 DOI: 10.1007/978-3-319-32805-8_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the clinical relevance of this approach.Targeted cancer therapies , also referred to as personalized medicine, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The use of monoclonal antibodies in colorectal and gastric cancer for example have shown best outcome when combined with chemotherapy, even though single agent anti-EGFR antibodies seem to be active in particular setting of metastatic colorectal cancer patients. However, it is not well defined whether the addition of anti-VEGF - and anti-EGFR strategies to chemotherapy could improve outcome in those patients susceptible to colorectal cancer-related metastases resection. Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints, exemplified by the recently FDA-approved agent, Ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of Ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. This section attempts to discuss recent progress of targeted agents and in tackling a more general target applicable to gastrointestinal cancer .
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27
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Carter JH, Cottrell CE, McNulty SN, Vigh-Conrad KA, Lamp S, Heusel JW, Duncavage EJ. FGFR2 amplification in colorectal adenocarcinoma. Cold Spring Harb Mol Case Stud 2017; 3:mcs.a001495. [PMID: 28835367 PMCID: PMC5701301 DOI: 10.1101/mcs.a001495] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 05/30/2017] [Indexed: 01/13/2023] Open
Abstract
FGFR2 is recurrently amplified in 5% of gastric cancers and 1%–4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.
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Affiliation(s)
- Jamal H Carter
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Catherine E Cottrell
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri 63130, USA.,Department of Genetics, Washington University in St. Louis, Missouri 63130, USA
| | - Samantha N McNulty
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri 63130, USA
| | | | - Stephen Lamp
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri 63130, USA
| | - Jonathan W Heusel
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri 63130, USA.,Department of Genetics, Washington University in St. Louis, Missouri 63130, USA
| | - Eric J Duncavage
- Department of Pathology and Immunology, Washington University in St. Louis, Missouri 63130, USA
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28
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Tian X, Wei F, Wang L, Yu W, Zhang N, Zhang X, Han Y, Yu J, Ren X. Herceptin Enhances the Antitumor Effect of Natural Killer Cells on Breast Cancer Cells Expressing Human Epidermal Growth Factor Receptor-2. Front Immunol 2017; 8:1426. [PMID: 29163501 PMCID: PMC5670328 DOI: 10.3389/fimmu.2017.01426] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 10/13/2017] [Indexed: 11/13/2022] Open
Abstract
Optimal adoptive cell therapy (ACT) should contribute to effective cancer treatment. The unique ability of natural killer (NK) cells to kill cancer cells independent of major histocompatibility requirement makes them suitable as ACT tools. Herceptin, an antihuman epidermal growth factor receptor-2 (anti-HER2) monoclonal antibody, is used to treat HER2+ breast cancer. However, it has limited effectiveness and possible severe cardiotoxicity. Given that Herceptin may increase the cytotoxicity of lymphocytes, we explored the possible augmentation of NK cell cytotoxicity against HER2+ breast cancer cells by Herceptin. We demonstrated that Herceptin could interact with CD16 on NK cells to expand the cytotoxic NK (specifically, CD56dim) cell population. Additionally, Herceptin increased NK cell migration and cytotoxicity against HER2+ breast cancer cells. In a pilot study, Herceptin-treated NK cells shrunk lung nodular metastasis in a woman with HER2+ breast cancer who could not tolerate the cardiotoxic side effects of Herceptin. Our findings support the therapeutic potential of Herceptin-treated NK cells in patients with HER2+ and Herceptin-intolerant breast cancer.
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Affiliation(s)
- Xiao Tian
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Feng Wei
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Limei Wang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Naining Zhang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Xinwei Zhang
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Ying Han
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Jinpu Yu
- National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Cancer Molecular Diagnostic Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center of Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
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29
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Gregório AC, Lacerda M, Figueiredo P, Simões S, Dias S, Moreira JN. Therapeutic Implications of the Molecular and Immune Landscape of Triple-Negative Breast Cancer. Pathol Oncol Res 2017; 24:701-716. [PMID: 28913723 DOI: 10.1007/s12253-017-0307-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 09/04/2017] [Indexed: 12/15/2022]
Abstract
Treatment and management of breast cancer imposes a heavy burden on public health care, and incidence rates continue to increase. Breast cancer is the most common female neoplasia and primary cause of death among women worldwide. The recognition of breast cancer as a complex and heterogeneous disease, comprising different molecular entities, was a landmark in our understanding of this malignancy. Valuing the impact of the molecular characteristics on tumor behavior enabled a better assessment of a patient's prognosis and increased the predictive power to therapeutic response and clinical outcome. Molecular heterogeneity is also prominent in the triple-negative breast cancer subtype, and is reflected by the distinct prognostic and patient's sensitivity to treatment, being chemotherapy the only systemic treatment currently available. From a therapeutic perspective, gene expression profiling of triple-negative tumors has notably contributed to the exploration of new druggable targets and brought to light the need to align these patients to the various therapies according to their triple-negative subtype. Additionally, the higher amount of tumor infiltrating lymphocytes, and the prevalence of an increased expression of PD-1 receptor and its ligand, PD-L1, in triple-negative tumors, created a new treatment opportunity with immune checkpoint inhibitors. This manuscript addresses the current knowledge on the molecular and immune profiles of breast cancer, and its impact on the development of targeted therapies, with a particular emphasis on the triple-negative subtype.
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Affiliation(s)
- Ana C Gregório
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal
- IIIUC - Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Manuela Lacerda
- IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Paulo Figueiredo
- IPOFG-EPE - Portuguese Institute of Oncology Francisco Gentil, Coimbra, Portugal
| | - Sérgio Simões
- FFUC - Faculty of Pharmacy, Pólo das Ciências da Saúde, University of Coimbra, Coimbra, Portugal
| | - Sérgio Dias
- IMM - Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - João Nuno Moreira
- CNC - Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I), University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal.
- FFUC - Faculty of Pharmacy, Pólo das Ciências da Saúde, University of Coimbra, Coimbra, Portugal.
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Kinnear C, Moore TL, Rodriguez-Lorenzo L, Rothen-Rutishauser B, Petri-Fink A. Form Follows Function: Nanoparticle Shape and Its Implications for Nanomedicine. Chem Rev 2017; 117:11476-11521. [DOI: 10.1021/acs.chemrev.7b00194] [Citation(s) in RCA: 342] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Calum Kinnear
- Bio21 Institute & School of Chemistry, University of Melbourne, Parkville 3010, Australia
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D'Andrea MR, Howanski RJ, Saller CF. MAP2 IHC detection: a marker of antigenicity in CNS tissues. Biotech Histochem 2017; 92:363-373. [PMID: 28766965 DOI: 10.1080/10520295.2017.1295169] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Immunohistochemistry (IHC) is used to detect antibody-specific antigens in tissues; the results depend on the ability of the primary antibodies to bind to their antigens. Therefore, results depend on the quality of preservation of the specimen. Many investigators have overcome the deleterious effects of over-fixation on the binding of primary antibodies to specimen antigens using IHC, but if the specimen is under-fixed or fixation is delayed, false negative results could be obtained despite certified laboratory practices. Microtubule-associated protein 2 (MAP2) is an abundant microtubule-associate protein that participates in the outgrowth of neuronal processes and synaptic plasticity; it is localized primarily in cell bodies and dendrites of neurons. MAP2 immunolabeling has been reported to be absent in areas of the entorhinal cortex and hippocampus of Alzheimer's disease brains that were co-localized with the dense-core type of amyloid plaques. It was hypothesized that the lack of MAP2 immunolabeling in these structures was due to the degradation of the MAP2 antigen by the neuronal proteases that were released as the neurons lysed leading to the formation of these plaques. Because MAP2 is sensitive to proteolysis, we hypothesized that changes in MAP2 immunolabeling may be correlated with the degree of fixation of central nervous system (CNS) tissues. We detected normal MAP2 immunolabeling in fixed rat brain tissues, but MAP2 immunolabeling was decreased or lost in unfixed and delayed-fixed rat brain tissues. By contrast, two ubiquitous CNS-specific markers, myelin basic protein and glial fibrillary acidic protein, were unaffected by the degree of fixation in the same tissues. Our observations suggest that preservation of various CNS-specific antigens differs with the degree of fixation and that the lack of MAP2 immunolabeling in the rat brain may indicate inadequate tissue fixation. We recommend applying MAP2 IHC for all CNS tissues as a pre-screen to assess the quality of the tissue preservation and to avoid potentially false negative IHC results.
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Affiliation(s)
| | - R J Howanski
- b Analytical Biological Services Inc. , Wilmington , Delaware
| | - C F Saller
- b Analytical Biological Services Inc. , Wilmington , Delaware
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Ahn S, Hong M, Van Vrancken M, Lyou YJ, Kim ST, Park SH, Kang WK, Park YS, Jung SH, Woo M, Lee J, Kim KM. A nCounter CNV Assay to Detect HER2 Amplification: A Correlation Study with Immunohistochemistry and In Situ Hybridization in Advanced Gastric Cancer. Mol Diagn Ther 2017; 20:375-83. [PMID: 27179810 DOI: 10.1007/s40291-016-0205-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIM Screening amplified genes for targeted therapy with high-throughput technology is very important. The NanoString nCounter system allows multiplexed digital quantification of target molecules through the use of color-coded barcodes with the great advantage that formalin-fixed, paraffin-embedded (FFPE) tissue can be utilized. METHODS We tested nCounter custom copy number variation (CNV) panels in 220 gastric cancer samples and evaluated the utility of this method as a screening tool for the detection of CNV using HER2. For the validation of results, we compared the nCounter results with immunohistochemistry (IHC), and we further performed in situ hybridization (ISH) in discrepant cases. RESULTS The average HER2 gene copy numbers (CNs) by nCounter were 17.25, 2.0 and 2.61 for the HER2 IHC positive (3+), equivocal (2+), and negative cases, respectively. Out of the 16 IHC 3+ cases, 13 (81.3 %) were reported as HER2 CN gain (≥4). Gastric cancers with homogeneous HER2 overexpression or high tumor purity showed HER2 CN ≥10. Among the 192 cases with HER2 IHC negative and without HER2 gene amplification, 29 showed a HER2 CN ≥4 with the nCounter assay. The nCounter assay had a concordance rate of 83.4 % (kappa value, 0.35), a sensitivity of 66.7 %, a specificity of 85.2 %, a negative predictive value of 96 %, and a positive predictive value of 32.6 % compared with HER2 IHC/ISH results. Fresh frozen (FF) samples revealed a higher concordance rate (91.5 %, kappa value, 0.59) than FFPE samples (78.5 %, kappa value 0.27) and showed a high specificity (97.2 %). CONCLUSION The nCounter CNV assay is a reliable and practical method to detect high CN variations. Given the intra-tumoral HER2 heterogeneity and normal cell contamination, additional IHC and/or FISH is necessary and needs caution in interpretation, especially in FFPE tissue samples.
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Affiliation(s)
- Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.,Center of Companion Diagnostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mineui Hong
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Korea
| | - Michael Van Vrancken
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - You Jeong Lyou
- Center of Companion Diagnostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea
| | - Se Hoon Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea
| | - Won Ki Kang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea
| | - Young Suk Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea
| | - Sin-Ho Jung
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Minah Woo
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea. .,Center of Companion Diagnostics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Statz CM, Patterson SE, Mockus SM. Barriers preventing the adoption of comprehensive cancer genomic profiling in the clinic. Expert Rev Mol Diagn 2017; 17:549-555. [DOI: 10.1080/14737159.2017.1319280] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Cannon TM, Shah AT, Skala MC. Autofluorescence imaging captures heterogeneous drug response differences between 2D and 3D breast cancer cultures. BIOMEDICAL OPTICS EXPRESS 2017; 8:1911-1925. [PMID: 28663873 PMCID: PMC5480588 DOI: 10.1364/boe.8.001911] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 02/02/2017] [Accepted: 02/12/2017] [Indexed: 05/13/2023]
Abstract
Two-photon microscopy of cellular autofluorescence intensity and lifetime (optical metabolic imaging, or OMI) is a promising tool for preclinical drug development. OMI, which exploits the endogenous fluorescence from the metabolic coenzymes NAD(P)H and FAD, is sensitive to changes in cell metabolism produced by drug treatment. Previous studies have shown that drug response, genetic expression, cell-cell communication, and cell signaling in 3D culture match those of the original in vivo tumor, but not those of 2D culture. The goal of this study is to use OMI to quantify dynamic cell-level metabolic differences in drug response in 2D cell lines vs. 3D organoids generated from xenograft tumors of the same cell origin. BT474 cells and Herceptin-resistant BT474 (HR6) cells were tested. Cells were treated with vehicle control, Herceptin, XL147 (PI3K inhibitor), and the combination. The OMI index was used to quantify response, and is a linear combination of the redox ratio (intensity of NAD(P)H divided by FAD), mean NADH lifetime, and mean FAD lifetime. The results confirm that the OMI index resolves significant differences (p<0.05) in drug response for 2D vs. 3D cultures, specifically for BT474 cells 24 hours after Herceptin treatment, for HR6 cells 24 and 72 hours after combination treatment, and for HR6 cells 72 hours after XL147 treatment. Cell-level analysis of the OMI index also reveals differences in the number of cell sub-populations in 2D vs. 3D culture at 24, 48, and 72 hours post-treatment in control and treated groups. Finally, significant increases (p<0.05) in the mean lifetime of NADH and FAD were measured in 2D vs. 3D for both cell lines at 72 hours post-treatment in control and all treatment groups. These whole-population differences in the mean NADH and FAD lifetimes are supported by differences in the number of cell sub-populations in 2D vs. 3D. Overall, these studies confirm that OMI is sensitive to differences in drug response in 2D vs. 3D, and provides further information on dynamic changes in the relative abundance of metabolic cell sub-populations that contribute to this difference.
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Affiliation(s)
- T. M. Cannon
- Department of Biomedical Engineering, Vanderbilt University, Station B, Box 1631, Nashville, TN 37235, USA
| | - A. T. Shah
- Department of Biomedical Engineering, Vanderbilt University, Station B, Box 1631, Nashville, TN 37235, USA
| | - M. C. Skala
- Morgridge Institute for Research, University of Wisconsin—Madison, 330 North Orchard Street, Madison, WI 53715, USA
- Department of Biomedical Engineering, University of Wisconsin—Madison, 1415 Engineering Drive, Madison, WI 53706, USA
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Rennhack J, To B, Wermuth H, Andrechek ER. Mouse Models of Breast Cancer Share Amplification and Deletion Events with Human Breast Cancer. J Mammary Gland Biol Neoplasia 2017; 22:71-84. [PMID: 28124185 PMCID: PMC5313323 DOI: 10.1007/s10911-017-9374-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 01/17/2017] [Indexed: 11/25/2022] Open
Abstract
Breast tumor heterogeneity has been well documented through the use of multiplatform -omic studies in human tumors. However, there is no integrative database to capture the heterogeneity within mouse models of breast cancer. This project identifies genomic copy number alterations (CNAs) in 600 tumors across 27 major mouse models of breast cancer through the application of a predictive algorithm to publicly available gene expression data. It was found that despite the presence of strong oncogenic drivers in most mouse models, CNAs are extremely common but heterogeneous both between models and within models. Many mouse CNA events are largely conserved in human tumors and in the mouse we show that they are associated with secondary tumor characteristics such as tumor histology, metastasis, as well as enhanced oncogenic signaling. These data serve as an important resource in guiding investigators when choosing a mouse model to understand the gene copy number changes relevant to human breast cancer.
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Affiliation(s)
- Jonathan Rennhack
- Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA
| | - Briana To
- Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA
| | - Harrison Wermuth
- Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA
| | - Eran R Andrechek
- Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA.
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Pan HD, Peng YF, Xiao G, Gu J. High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis. World J Gastroenterol 2017; 23:1233-1240. [PMID: 28275303 PMCID: PMC5323448 DOI: 10.3748/wjg.v23.i7.1233] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/13/2016] [Accepted: 01/03/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To develop predictive markers in blood for colorectal cancer liver metastasis.
METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was IIIC (T3-4N2M0), while another 10 patients with synchronous liver metastasis (TNM stage IV) were recruited for group B. During the surgical procedure, a 10-mL drainage vein (DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-mL peripheral vein (PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.
RESULTS Univariate analysis revealed that platelet-derived growth factor AA (PDGFAA) in DV blood (dPDGFAA) (P = 0.001), PDGFAA in PV blood (pPDGFAA) (P = 0.007), and human epidermal growth factor receptor-2 in PV blood (pHER2) (P = 0.001), pMMP7 (P = 0.028), pRANTES (P = 0.013), and pEGF (P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified dPDGFAA (HR = 1.001, P = 0.033) and pHER2 (HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance (P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA (r = 0.794, P < 0.001), but not for HER2 (r = 0.189, P = 0.424).
CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.
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Ding XF, Li LF, Zhou XL, Guo LN, Dou MM, Chi YY, Wu SX, Zhang YN, Shan ZZ, Zhang YJ, Wang F, Fan QX, Zhao J, Sun TW. P-mTOR Expression and Implication in Breast Carcinoma: A Systematic Review and Meta-Analysis. PLoS One 2017; 12:e0170302. [PMID: 28114374 PMCID: PMC5256929 DOI: 10.1371/journal.pone.0170302] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/03/2017] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Phosphorylated mammalian target of rapamycin (p-mTOR) is a promising prognostic marker in many types of cancer. However, its survival benefit in patients with breast carcinoma remains unknown. The aim of the present study was to assess the relationship between p-mTOR expression and prognosis in breast carcinoma based on a systematic review and meta-analysis. MATERIALS AND METHODS Electronic databases (including Pubmed, Embase, ISI web of science, and Cochrane Library) were searched up to November 24, 2015. The outcome measures were hazard ratios (HRs) with 95% confidence interval (CI) for the association between the prognosis of breast carcinoma patients and p-mTOR expression. Primary end points were disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS). Statistical analysis was performed with STATA 12.0. RESULTS Nine cohort studies including 3051 patients met full eligibility criteria. The pooled HRs (95% CI) for OS, DFS, and RFS were 0.84 (0.27-2.63), 0.71 (0.40-1.23), and 0.48 (0.20-1.18), respectively. CONCLUSIONS Our findings suggested that p-mTOR overexpression was not significantly related to prognosis in breast carcinoma regarding OS and disease recurrence. Prospective studies are warranted to examine the association between p-mTOR expression and survival outcomes in breast carcinoma.
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Affiliation(s)
- Xian-Fei Ding
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Feng Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xue-Liang Zhou
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li-Na Guo
- Department of Gerontology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Meng-Meng Dou
- Department of Integrated Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yan-Yan Chi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shao-Xuan Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ya-Na Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zheng-Zheng Shan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yi-Jie Zhang
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Feng Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qing-Xia Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tong-Wen Sun
- Department of General ICU, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Ma Z, Parris AB, Xiao Z, Howard EW, Kosanke SD, Feng X, Yang X. Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:6. [PMID: 28061785 PMCID: PMC5217213 DOI: 10.1186/s13046-016-0479-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 12/16/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER+ breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2+ breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure. The tolerance to high dose/long-term drug administration may hinder its potential in clinical settings. Therefore, we aimed to test a novel, short-term chemopreventative strategy using lapatinib during the premalignant risk window in MMTV-erbB-2 mice. METHODS We initially treated cultured cells with lapatinib to explore the anti-proliferative effects of lapatinib in vitro. We used a syngeneic tumor graft model to begin exploring the in vivo anti-tumorigenic effects of lapatinib in MMTV-erbB-2 mice. Then, we tested the efficacy of brief exposure to lapatinib (100 mg/kg/day for 8 weeks), beginning at 16 weeks of age, in the prevention of mammary tumor development in MMTV-erbB-2 mice. RESULTS In the syngeneic tumor transplant model, we determined that lapatinib significantly inhibited tumor cell proliferation. Furthermore, we demonstrated that short-term lapatinib exposure resulted in life-long protective effects, as supported by increased tumor latency in lapatinib-treated mice compared to the control mice. We further established that delayed tumor development in the treated mice was preceded by decreased BrdU nuclear incorporation and inhibited mammary morphogenesis. Molecular analysis indicated that lapatinib inhibited phosphorylation and expression of EGFR, erbB-3, erbB-2, Akt1, and Erk1/2 in premalignant mammary tissues. Also, lapatinib drastically inhibited the phosphorylation and expression of ERα and the transcription of ER target genes in premalignant mammary tissues. We also determined that lapatinib suppressed the stemness of breast cancer cell lines, as evidenced by decreased tumorsphere formation and ALDH+ cell populations. CONCLUSIONS Taken together, these data demonstrate that brief treatment with EGFR/erbB-2-targeting agents before the onset of tumors may provide lifelong protection from mammary tumors, through the concurrent inhibition of erbB-2 and ER signaling pathways and consequential reprogramming. Our findings support further clinical testing to explore the benefit of shorter lapatinib exposure in the prevention of erbB-2-mediated carcinogenesis.
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Affiliation(s)
- Zhikun Ma
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA.,Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China
| | - Amanda B Parris
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA
| | - Zhengzheng Xiao
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA
| | - Erin W Howard
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA
| | - Stanley D Kosanke
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Xiaoshan Feng
- Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China
| | - Xiaohe Yang
- Julius L. Chambers Biomedical/Biotechnology Research Institute, Department of Biological and Biomedical Sciences, North Carolina Central University, 500 Laureate Way, Room 4301, Kannapolis, NC, 28081, USA. .,Department of Oncology, First Affiliated Hospital of Henan University of Sciences and Technology, Luoyang, China.
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Hou Y, Nitta H, Li Z. HER2 Gene Protein Assay Is Useful to Determine HER2 Status and Evaluate HER2 Heterogeneity in HER2 Equivocal Breast Cancer. Am J Clin Pathol 2017; 147:89-95. [PMID: 28110280 DOI: 10.1093/ajcp/aqw211] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVES Approximately 15% of breast cancers show equivocal human epidermal growth factor receptor 2 (HER2) results on HER2 immunohistochemistry (IHC) and are reflexed for fluorescence in situ hybridization (FISH). However, some cases remain equivocal. In this study, we evaluated these double-equivocal cases by using a novel gene protein assay (GPA), which can simultaneously assess HER2 gene copy number and protein on a single slide using bright-field microscopy. METHODS GPA was performed on 42 HER2 IHC and FISH double-equivocal cases. RESULTS GPA was negative for amplification in 28 cases, equivocal in three cases, and positive in 11 cases. The GPA results showed excellent concordance with either repeat FISH using a chromosome 17 centromere probe or FISH using an alternative probe. Furthermore, HER2 heterogeneity was identified in three of 11 GPA-positive cases. CONCLUSIONS HER2 GPA performs accurately and is very useful to determine HER2 status in HER2 IHC and FISH double-equivocal breast cancer cases and identify HER2 heterogeneity.
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Affiliation(s)
- Yanjun Hou
- From the Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus
| | | | - Zaibo Li
- From the Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus
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Jha T, Adhikari N, Halder AK, Saha A. Ligand- and Structure-Based Drug Design of Non-Steroidal Aromatase Inhibitors (NSAIs) in Breast Cancer. Oncology 2017. [DOI: 10.4018/978-1-5225-0549-5.ch004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Aromatase is a multienzyme complex overexpressed in breast cancer and responsible for estrogen production. It is the potential target for designing anti-breast cancer drugs. Ligand and Structure-Based Drug Designing approaches (LBDD and SBDD) are involved in development of active and more specific Nonsteroidal Aromatase Inhibitors (NSAIs). Different LBDD and SBDD approaches are presented here to understand their utility in designing novel NSAIs. It is observed that molecules should possess a five or six membered heterocyclic nitrogen containing ring to coordinate with heme portion of aromatase for inhibition. Moreover, one or two hydrogen bond acceptor features, hydrophobicity, and steric factors may play crucial roles for anti-aromatase activity. Electrostatic, van der Waals, and p-p interactions are other important factors that determine binding affinity of inhibitors. HQSAR, LDA-QSAR, GQSAR, CoMFA, and CoMSIA approaches, pharmacophore mapping followed by virtual screening, docking, and dynamic simulation may be effective approaches for designing new potent anti-aromatase molecules.
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Ait-Oudhia S, Ovacik MA, Mager DE. Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity. MAbs 2017; 9:15-28. [PMID: 27661132 PMCID: PMC5240652 DOI: 10.1080/19420862.2016.1238995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 09/02/2016] [Accepted: 09/14/2016] [Indexed: 10/21/2022] Open
Abstract
Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro- and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets. Such complexities can be addressed through the use of robust computational modeling techniques that have proven powerful tools for pragmatic characterization of experimental data and for theoretical exploration of antibody efficacy and adverse effects. The primary objectives of such multi-scale mathematical models are to generate and test competing hypotheses and to predict clinical outcomes. In this review, relevant systems pharmacology and enhanced PD (ePD) models that are used as predictive tools for antibody-based drug action are reported. Their common conceptual features are highlighted, along with approaches used for modeling preclinical and clinically available data. Key examples illustrate how systems pharmacology and ePD models codify the interplay among complex biology, drug concentrations, and pharmacological effects. New hybrid modeling concepts that bridge cutting-edge systems pharmacology models with established PK/ePD models will be needed to anticipate antibody effects on disease in subpopulations and individual patients.
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Affiliation(s)
- Sihem Ait-Oudhia
- Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Meric Ayse Ovacik
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Donald E. Mager
- Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
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Yoon HJ, Kim KH, Kim JY, Park HJ, Cho JY, Hong YJ, Park HW, Kim JH, Ahn Y, Jeong MH, Cho JG, Park JC. Chemotherapy-Induced Left Ventricular Dysfunction in Patients with Breast Cancer. J Breast Cancer 2016; 19:402-409. [PMID: 28053628 PMCID: PMC5204046 DOI: 10.4048/jbc.2016.19.4.402] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/02/2016] [Indexed: 01/03/2023] Open
Abstract
Purpose As the numbers of cancer cases and survivors increase, the incidence and natural history of chemotherapy-induced cardiotoxicities in patients with breast cancer may also be expected to change. The present study aimed to investigate the incidence and predictors of chemotherapy-induced left ventricular dysfunction (LVD) in patients with breast cancer. Methods From 2003 to 2010, 712 female patients with breast cancer (55.7±10.7 years) were enrolled and divided into the LVD group (n=82, 56.7±10.1 years) and the non-LVD group (n=630, 55.6±10.8 years). Baseline clinical and treatment-related variables were compared. Results Chemotherapy-induced LVD developed in 82 cases (11.4%). Low body mass index (BMI), low triglyceride level, advanced cancer stage, and the use of doxorubicin, paclitaxel, trastuzumab, or radiotherapy were significant predictors of LVD in a univariate analysis. In a multivariate analysis, low BMI, advanced cancer stage, and the use of target therapy with trastuzumab were independent predictors of chemotherapy-induced LVD. Chemotherapy-induced LVD was recovered in 53 patients (64.6%), but left ventricular function was not recovered in 29 patients (35.4%). Conclusion Chemotherapy-induced LVD was not uncommon and did not reduce in many of our patients with breast cancer. Low BMI, advanced cancer stage, and the use of trastuzumab were independent predictors of chemotherapy-induced LVD in patients with breast cancer. The development of chemotherapy-induced LVD should be carefully monitored in patients with breast cancer who are receiving trastuzumab therapy, have poor nutritional status, and advanced cancer stage.
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Affiliation(s)
- Hyun Ju Yoon
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Kye Hun Kim
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Jong Yoon Kim
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Hyuk Jin Park
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Jae Yeong Cho
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Young Joon Hong
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Hyung Wook Park
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Ju Han Kim
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Youngkeun Ahn
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Myung Ho Jeong
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Jeong Gwan Cho
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
| | - Jong Chun Park
- Department of Cardiovascular Medicine, Chonnam National University Hospital, and Research Institute of Medical Science, Chonnam National University Medical School, Gwangju, Korea
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Lv Q, Meng Z, Yu Y, Jiang F, Guan D, Liang C, Zhou J, Lu A, Zhang G. Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer. Int J Mol Sci 2016; 17:E2095. [PMID: 27983617 PMCID: PMC5187895 DOI: 10.3390/ijms17122095] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/15/2016] [Accepted: 12/01/2016] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the second leading cause of cancer death among women. Human epidermal receptor 2 (HER2) positive breast cancer (HER2+ BC) is the most aggressive subtype of breast cancer, with poor prognosis and a high rate of recurrence. About one third of breast cancer is HER2+ BC with significantly high expression level of HER2 protein compared to other subtypes. Therefore, HER2 is an important biomarker and an ideal target for developing therapeutic strategies for the treatment HER2+ BC. In this review, HER2 structure and physiological and pathological roles in HER2+ BC are discussed. Two diagnostic tests, immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), for evaluating HER2 expression levels are briefly introduced. The current mainstay targeted therapies for HER2+ BC include monoclonal antibodies, small molecule tyrosine kinase inhibitors, antibody-drug conjugates (ADC) and other emerging anti-HER2 agents. In clinical practice, combination therapies are commonly adopted in order to achieve synergistic drug response. This review will help to better understand the molecular mechanism of HER2+ BC and further facilitate the development of more effective therapeutic strategies against HER2+ BC.
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Affiliation(s)
- Quanxia Lv
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Ziyuan Meng
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Yuanyuan Yu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Feng Jiang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
- The State Key Laboratory Base of Novel Functional Materials and Preparation Science, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China.
| | - Daogang Guan
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Chao Liang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Junwei Zhou
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
| | - Aiping Lu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong 999077, China.
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU (Haimen) Institute of Science and Technology (IST), Haimen 226133, China.
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Mao L, Sun AJ, Wu JZ, Tang JH. Involvement of microRNAs in HER2 signaling and trastuzumab treatment. Tumour Biol 2016; 37:15437–15446. [PMID: 27734339 DOI: 10.1007/s13277-016-5405-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 09/13/2016] [Indexed: 12/21/2022] Open
Abstract
The prognostic value of HER2 has been demonstrated in many human cancer types such us breast cancer, gastric cancer and ovarian cancer. Trastuzumab is the first anti-HER2 monoclonal antibody that has remarkably improved outcomes of patients with HER2-positive breast cancer. For HER2-positive metastatic gastric cancers, the addition of trastuzumab to traditional chemotherapy also significantly prolonged overall survival. However, intrinsic and acquired resistance to trastuzumab is common and results in disease progression. HER2 signaling network and mechanisms underlying the resistance have been broadly investigated in order to develop strategy to overcome the dilemma. Increasing evidence indicates that microRNAs (miRNA), a group of small non-coding RNAs, are involved in HER2 signaling and trastuzumab treatment. This review summarizes all the miRNAs that target HER2 and describes their activity on biological processes. Moreover, miRNAs that regulate trastuzumab resistance and relevant molecular mechanisms are highlighted. MiRNA signatures associated with HER2, miRNAs that mediate trastuzumab activity, and potential miRNA biomarkers of trastuzumab sensitivity are also discussed.
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Affiliation(s)
- Ling Mao
- Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
- Department of Thyroid and Breast Surgery, Huai'an Second People's Hospital, Xuzhou medical university, Huai'an, China
| | - Ai-Jun Sun
- Department of Thyroid and Breast Surgery, Huai'an Second People's Hospital, Xuzhou medical university, Huai'an, China
| | - Jian-Zhong Wu
- Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
| | - Jin-Hai Tang
- Department of General Surgery, the Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, 42Bai Zi Ting Road, Nanjing, Jiangsu, 210000, China.
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Kameswaran M, Gota V, Ambade R, Gupta S, Dash A. Preparation and preclinical evaluation of 131 I-trastuzumab for breast cancer. J Labelled Comp Radiopharm 2016; 60:12-19. [PMID: 27813128 DOI: 10.1002/jlcr.3465] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 08/30/2016] [Accepted: 09/08/2016] [Indexed: 11/10/2022]
Abstract
Trastuzumab that targets the human epidermal growth factor receptor type 2 (HER2) is known to benefit patients with HER2+ metastatic breast cancer. The objective was to explore the potential of 131 I-trastuzumab for treatment of breast cancers. Radioiodination of trastuzumab was carried out by chloramine-T method, purified by using PD-10 column, and characterized by size exclusion high-performance liquid chromatography on a gel column. In vitro studies were carried out in HER2+ cells to determine the specificity of the radioimmunoconjugate. Uptake and retention of 131 I-trastuzumab were determined by biodistribution studies in tumor-bearing non-obese diabetic/severe combined immunodeficiency and normal severe combined immunodeficiency mice. The radiochemical purity (RCP) of 131 I-trastuzumab was 98 ± 0.4% with retention time of 17 minutes by high-performance liquid chromatography. In vitro stability studies exhibited RCP of more than 90% in serum at 37°C after 120 hours of radioiodination. In vitro cell binding with 131 I-trastuzumab in HER2+ cells showed binding of 28% to 35% which was inhibited significantly, with unlabeled trastuzumab confirming its specificity. Kd value of 131 I-trastuzumab was 0.5 nM, while its immunoreactivity was more than 80%. Uptake of more than 12% and retention were observed in the tumors up to 120 hours p.i. 131 I-trastuzumab prepared in-house-exhibited RCP of more than 98%, excellent immunoreactivity, affinity to HER2+ cell lines and good tumor uptake thereby indicating its potential for further evaluation in HER2+ breast cancers.
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Affiliation(s)
- Mythili Kameswaran
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Vikram Gota
- Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India
| | - Rajwardhan Ambade
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Sudeep Gupta
- Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Navi Mumbai, India
| | - Ashutosh Dash
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India
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Barajas RF, Krohn KA, Link JM, Hawkins RA, Clarke JL, Pampaloni MH, Cha S. Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine. Biomedicines 2016; 4:biomedicines4040024. [PMID: 28536391 PMCID: PMC5344267 DOI: 10.3390/biomedicines4040024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/27/2016] [Accepted: 10/29/2016] [Indexed: 01/17/2023] Open
Abstract
The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring.
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Affiliation(s)
- Ramon F Barajas
- Department of Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
- Advanced Imaging Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
| | - Kenneth A Krohn
- Department of Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
- Radiochemistry Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
| | - Jeanne M Link
- Department of Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
- Radiochemistry Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
| | - Randall A Hawkins
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, M-391, San Francisco, CA 94143-0628, USA.
| | - Jennifer L Clarke
- Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave., Room 779 M, San Francisco, CA 94143-0112, USA.
| | - Miguel H Pampaloni
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, M-391, San Francisco, CA 94143-0628, USA.
| | - Soonmee Cha
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, M-391, San Francisco, CA 94143-0628, USA.
- Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave., Room 779 M, San Francisco, CA 94143-0112, USA.
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Samineni D, Girish S, Li C. Impact of Shed/Soluble targets on the PK/PD of approved therapeutic monoclonal antibodies. Expert Rev Clin Pharmacol 2016; 9:1557-1569. [DOI: 10.1080/17512433.2016.1243055] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 2016; 8:725-734. [PMID: 27795812 PMCID: PMC5064050 DOI: 10.4251/wjgo.v8.i10.725] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.
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Nocera NF, Lee MC, De La Cruz LM, Rosemblit C, Czerniecki BJ. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention. Front Pharmacol 2016; 7:356. [PMID: 27766079 PMCID: PMC5052279 DOI: 10.3389/fphar.2016.00356] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/20/2016] [Indexed: 12/17/2022] Open
Abstract
The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.
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Affiliation(s)
- Nadia F. Nocera
- Department of Surgery, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA
| | - M. Catherine Lee
- Comprehensive Breast Program, H. Lee Moffitt Cancer CenterTampa, FL, USA
| | - Lucy M. De La Cruz
- Department of Surgery, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA
| | - Cinthia Rosemblit
- Department of Surgery, University of Pennsylvania Perelman School of MedicinePhiladelphia, PA, USA
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Tiwari SR, Mishra P, Abraham J. Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Clin Breast Cancer 2016; 16:344-348. [DOI: 10.1016/j.clbc.2016.05.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/17/2016] [Accepted: 05/23/2016] [Indexed: 11/17/2022]
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