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Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models
In head and neck squamous cell cancer, the human epidermal growth factor receptor 1 (EGFR) is the dominant signaling molecule among all members of the family. So far, cetuximab is the only approved anti-EGFR monoclonal antibody used for the treatment of head and neck squamous cell cancer, but despit...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society of Nuclear Medicine
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424230/ https://www.ncbi.nlm.nih.gov/pubmed/30213849 http://dx.doi.org/10.2967/jnumed.118.216069 |
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author | Burley, Thomas A. Da Pieve, Chiara Martins, Carlos D. Ciobota, Daniela M. Allott, Louis Oyen, Wim J.G Harrington, Kevin J. Smith, Graham Kramer-Marek, Gabriela |
author_facet | Burley, Thomas A. Da Pieve, Chiara Martins, Carlos D. Ciobota, Daniela M. Allott, Louis Oyen, Wim J.G Harrington, Kevin J. Smith, Graham Kramer-Marek, Gabriela |
author_sort | Burley, Thomas A. |
collection | PubMed |
description | In head and neck squamous cell cancer, the human epidermal growth factor receptor 1 (EGFR) is the dominant signaling molecule among all members of the family. So far, cetuximab is the only approved anti-EGFR monoclonal antibody used for the treatment of head and neck squamous cell cancer, but despite the benefits of adding it to standard treatment regimens, attempts to define a predictive biomarker to stratify patients for cetuximab treatment have been unsuccessful. We hypothesized that imaging with EGFR-specific radioligands may facilitate noninvasive measurement of EGFR expression across the entire tumor burden and allow for dynamic monitoring of cetuximab-mediated changes in receptor expression. Methods: EGFR-specific Affibody molecule (Z(EGFR:03115)) was radiolabeled with (89)Zr and (18)F. The radioligands were characterized in vitro and in mice bearing subcutaneous tumors with varying levels of EGFR expression. The protein dose for imaging studies was assessed by injecting (89)Zr-deferoxamine-Z(EGFR:03115) (2.4–3.6 MBq, 2 μg) either together with or 30 min after increasing amounts of unlabeled Z(EGFR:03115) (1, 5, 10, 15, and 20 μg). PET images were acquired at 3, 24, and 48 h after injection, and the image quantification data were correlated with the biodistribution results. The EGFR expression and biodistribution of the tracer were assessed ex vivo by immunohistochemistry, Western blot, and autoradiography. To downregulate the EGFR level, treatment with cetuximab was performed, and (18)F-aluminium fluoride-NOTA-Z(EGFR:03115) (12 μg, 1.5–2 MBq/mouse) was used to monitor receptor changes. Results: In vivo studies demonstrated that coinjecting 10 μg of nonlabeled molecules with (89)Zr-deferoxamine-Z(EGFR:03115) allows for clear tumor visualization 3 h after injection. The radioconjugate tumor accumulation was EGFR-specific, and PET imaging data showed a clear differentiation between xenografts with varying EGFR expression levels. A strong correlation was observed between PET analysis, ex vivo estimates of tracer concentration, and receptor expression in tumor tissues. Additionally, (18)F-aluminium fluoride-NOTA-Z(EGFR:03115) could measure receptor downregulation in response to EGFR inhibition. Conclusion: Z(EGFR:03115)-based radioconjugates can assess different levels of EGFR level in vivo and measure receptor expression changes in response to cetuximab, indicating a potential for assessment of adequate treatment dosing with anti-EGFR antibodies. |
format | Online Article Text |
id | pubmed-6424230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Society of Nuclear Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-64242302019-03-26 Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models Burley, Thomas A. Da Pieve, Chiara Martins, Carlos D. Ciobota, Daniela M. Allott, Louis Oyen, Wim J.G Harrington, Kevin J. Smith, Graham Kramer-Marek, Gabriela J Nucl Med Clinical In head and neck squamous cell cancer, the human epidermal growth factor receptor 1 (EGFR) is the dominant signaling molecule among all members of the family. So far, cetuximab is the only approved anti-EGFR monoclonal antibody used for the treatment of head and neck squamous cell cancer, but despite the benefits of adding it to standard treatment regimens, attempts to define a predictive biomarker to stratify patients for cetuximab treatment have been unsuccessful. We hypothesized that imaging with EGFR-specific radioligands may facilitate noninvasive measurement of EGFR expression across the entire tumor burden and allow for dynamic monitoring of cetuximab-mediated changes in receptor expression. Methods: EGFR-specific Affibody molecule (Z(EGFR:03115)) was radiolabeled with (89)Zr and (18)F. The radioligands were characterized in vitro and in mice bearing subcutaneous tumors with varying levels of EGFR expression. The protein dose for imaging studies was assessed by injecting (89)Zr-deferoxamine-Z(EGFR:03115) (2.4–3.6 MBq, 2 μg) either together with or 30 min after increasing amounts of unlabeled Z(EGFR:03115) (1, 5, 10, 15, and 20 μg). PET images were acquired at 3, 24, and 48 h after injection, and the image quantification data were correlated with the biodistribution results. The EGFR expression and biodistribution of the tracer were assessed ex vivo by immunohistochemistry, Western blot, and autoradiography. To downregulate the EGFR level, treatment with cetuximab was performed, and (18)F-aluminium fluoride-NOTA-Z(EGFR:03115) (12 μg, 1.5–2 MBq/mouse) was used to monitor receptor changes. Results: In vivo studies demonstrated that coinjecting 10 μg of nonlabeled molecules with (89)Zr-deferoxamine-Z(EGFR:03115) allows for clear tumor visualization 3 h after injection. The radioconjugate tumor accumulation was EGFR-specific, and PET imaging data showed a clear differentiation between xenografts with varying EGFR expression levels. A strong correlation was observed between PET analysis, ex vivo estimates of tracer concentration, and receptor expression in tumor tissues. Additionally, (18)F-aluminium fluoride-NOTA-Z(EGFR:03115) could measure receptor downregulation in response to EGFR inhibition. Conclusion: Z(EGFR:03115)-based radioconjugates can assess different levels of EGFR level in vivo and measure receptor expression changes in response to cetuximab, indicating a potential for assessment of adequate treatment dosing with anti-EGFR antibodies. Society of Nuclear Medicine 2019-03 /pmc/articles/PMC6424230/ /pubmed/30213849 http://dx.doi.org/10.2967/jnumed.118.216069 Text en © 2019 by the Society of Nuclear Medicine and Molecular Imaging. Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml. |
spellingShingle | Clinical Burley, Thomas A. Da Pieve, Chiara Martins, Carlos D. Ciobota, Daniela M. Allott, Louis Oyen, Wim J.G Harrington, Kevin J. Smith, Graham Kramer-Marek, Gabriela Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title | Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title_full | Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title_fullStr | Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title_full_unstemmed | Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title_short | Affibody-Based PET Imaging to Guide EGFR-Targeted Cancer Therapy in Head and Neck Squamous Cell Cancer Models |
title_sort | affibody-based pet imaging to guide egfr-targeted cancer therapy in head and neck squamous cell cancer models |
topic | Clinical |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424230/ https://www.ncbi.nlm.nih.gov/pubmed/30213849 http://dx.doi.org/10.2967/jnumed.118.216069 |
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