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Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer

BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as...

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Autores principales: Morgenroth, Agnieszka, Tinkir, Ebru, Vogg, Andreas T. J., Sankaranarayanan, Ramya Ambur, Baazaoui, Fatima, Mottaghy, Felix M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805467/
https://www.ncbi.nlm.nih.gov/pubmed/31640747
http://dx.doi.org/10.1186/s13058-019-1205-1
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author Morgenroth, Agnieszka
Tinkir, Ebru
Vogg, Andreas T. J.
Sankaranarayanan, Ramya Ambur
Baazaoui, Fatima
Mottaghy, Felix M.
author_facet Morgenroth, Agnieszka
Tinkir, Ebru
Vogg, Andreas T. J.
Sankaranarayanan, Ramya Ambur
Baazaoui, Fatima
Mottaghy, Felix M.
author_sort Morgenroth, Agnieszka
collection PubMed
description BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT). METHODS: Tube formation was investigated after incubation of endothelial HUVEC cells in tumor-conditioned media and monitored after staining using microscopy. A binding study with (68)Ga-labeled PSMA-addressing ligand was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with radiolabeled PSMA-addressing ligand [(177)Lu]-PSMA-617. For in vivo experiments, NUDE mice were xenografted with triple-negative breast cancer cells MDA-MB231 or estrogen receptor expressing breast cancer cells MCF-7. Biodistribution and binding behavior of [(68)Ga]-PSMA-11 was investigated in both tumor models at 30 min post injection using μPET. PSMA- and CD31-specific staining was conducted to visualize PSMA expression and neovascularization in tumor tissue ex vivo. RESULTS: The triple-negative breast cancer cells MDA-MB231 showed a high pro-angiogenetic potential on tube formation of endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligands. (177)Lu-labeled PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by μPET, radiolabeled PSMA-ligand accumulated specifically in the triple-negative breast cancer xenograft MDA-MB231 (T/B ratio of 43.3 ± 0.9), while no [(68)Ga]-PSMA-11 was detected in the estrogen-sensitive MCF-7 xenograft (T/B ratio of 1.1 ± 0.1). An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft-associated endothelial cells and also on TNBC cells. CONCLUSIONS: Here we demonstrate PSMA as promising target for two-compartment endogenous radio-ligand therapy of triple-negative breast cancer.
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spelling pubmed-68054672019-10-24 Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer Morgenroth, Agnieszka Tinkir, Ebru Vogg, Andreas T. J. Sankaranarayanan, Ramya Ambur Baazaoui, Fatima Mottaghy, Felix M. Breast Cancer Res Research Article BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT). METHODS: Tube formation was investigated after incubation of endothelial HUVEC cells in tumor-conditioned media and monitored after staining using microscopy. A binding study with (68)Ga-labeled PSMA-addressing ligand was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with radiolabeled PSMA-addressing ligand [(177)Lu]-PSMA-617. For in vivo experiments, NUDE mice were xenografted with triple-negative breast cancer cells MDA-MB231 or estrogen receptor expressing breast cancer cells MCF-7. Biodistribution and binding behavior of [(68)Ga]-PSMA-11 was investigated in both tumor models at 30 min post injection using μPET. PSMA- and CD31-specific staining was conducted to visualize PSMA expression and neovascularization in tumor tissue ex vivo. RESULTS: The triple-negative breast cancer cells MDA-MB231 showed a high pro-angiogenetic potential on tube formation of endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligands. (177)Lu-labeled PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by μPET, radiolabeled PSMA-ligand accumulated specifically in the triple-negative breast cancer xenograft MDA-MB231 (T/B ratio of 43.3 ± 0.9), while no [(68)Ga]-PSMA-11 was detected in the estrogen-sensitive MCF-7 xenograft (T/B ratio of 1.1 ± 0.1). An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft-associated endothelial cells and also on TNBC cells. CONCLUSIONS: Here we demonstrate PSMA as promising target for two-compartment endogenous radio-ligand therapy of triple-negative breast cancer. BioMed Central 2019-10-22 2019 /pmc/articles/PMC6805467/ /pubmed/31640747 http://dx.doi.org/10.1186/s13058-019-1205-1 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Morgenroth, Agnieszka
Tinkir, Ebru
Vogg, Andreas T. J.
Sankaranarayanan, Ramya Ambur
Baazaoui, Fatima
Mottaghy, Felix M.
Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title_full Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title_fullStr Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title_full_unstemmed Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title_short Targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
title_sort targeting of prostate-specific membrane antigen for radio-ligand therapy of triple-negative breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805467/
https://www.ncbi.nlm.nih.gov/pubmed/31640747
http://dx.doi.org/10.1186/s13058-019-1205-1
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