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A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts
The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society of Nuclear Medicine
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126438/ https://www.ncbi.nlm.nih.gov/pubmed/29626120 http://dx.doi.org/10.2967/jnumed.118.210435 |
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author | Loktev, Anastasia Lindner, Thomas Mier, Walter Debus, Jürgen Altmann, Annette Jäger, Dirk Giesel, Frederik Kratochwil, Clemens Barthe, Philippe Roumestand, Christian Haberkorn, Uwe |
author_facet | Loktev, Anastasia Lindner, Thomas Mier, Walter Debus, Jürgen Altmann, Annette Jäger, Dirk Giesel, Frederik Kratochwil, Clemens Barthe, Philippe Roumestand, Christian Haberkorn, Uwe |
author_sort | Loktev, Anastasia |
collection | PubMed |
description | The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with (68)Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer (18)F-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with (68)Ga but also with therapeutic isotopes such as (177)Lu or (90)Y. |
format | Online Article Text |
id | pubmed-6126438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Society of Nuclear Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-61264382019-03-01 A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts Loktev, Anastasia Lindner, Thomas Mier, Walter Debus, Jürgen Altmann, Annette Jäger, Dirk Giesel, Frederik Kratochwil, Clemens Barthe, Philippe Roumestand, Christian Haberkorn, Uwe J Nucl Med Translational The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with (68)Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer (18)F-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with (68)Ga but also with therapeutic isotopes such as (177)Lu or (90)Y. Society of Nuclear Medicine 2018-09 /pmc/articles/PMC6126438/ /pubmed/29626120 http://dx.doi.org/10.2967/jnumed.118.210435 Text en © 2018 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 | Translational Loktev, Anastasia Lindner, Thomas Mier, Walter Debus, Jürgen Altmann, Annette Jäger, Dirk Giesel, Frederik Kratochwil, Clemens Barthe, Philippe Roumestand, Christian Haberkorn, Uwe A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title | A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title_full | A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title_fullStr | A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title_full_unstemmed | A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title_short | A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts |
title_sort | tumor-imaging method targeting cancer-associated fibroblasts |
topic | Translational |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126438/ https://www.ncbi.nlm.nih.gov/pubmed/29626120 http://dx.doi.org/10.2967/jnumed.118.210435 |
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