Cargando…

HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses

SIMPLE SUMMARY: The prognosis for advanced Extramammary Paget’s disease (EMPD) is almost always poor. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addr...

Descripción completa

Detalles Bibliográficos
Autores principales: Tokuchi, Keiko, Maeda, Takuya, Kitamura, Shinya, Yanagi, Teruki, Ujiie, Hideyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322551/
https://www.ncbi.nlm.nih.gov/pubmed/35884581
http://dx.doi.org/10.3390/cancers14143519
_version_ 1784756332767739904
author Tokuchi, Keiko
Maeda, Takuya
Kitamura, Shinya
Yanagi, Teruki
Ujiie, Hideyuki
author_facet Tokuchi, Keiko
Maeda, Takuya
Kitamura, Shinya
Yanagi, Teruki
Ujiie, Hideyuki
author_sort Tokuchi, Keiko
collection PubMed
description SIMPLE SUMMARY: The prognosis for advanced Extramammary Paget’s disease (EMPD) is almost always poor. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in cases with the ERBB2-mutation or ERBB2-overexpression. ABSTRACT: Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.
format Online
Article
Text
id pubmed-9322551
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93225512022-07-27 HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses Tokuchi, Keiko Maeda, Takuya Kitamura, Shinya Yanagi, Teruki Ujiie, Hideyuki Cancers (Basel) Article SIMPLE SUMMARY: The prognosis for advanced Extramammary Paget’s disease (EMPD) is almost always poor. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in cases with the ERBB2-mutation or ERBB2-overexpression. ABSTRACT: Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases. MDPI 2022-07-20 /pmc/articles/PMC9322551/ /pubmed/35884581 http://dx.doi.org/10.3390/cancers14143519 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tokuchi, Keiko
Maeda, Takuya
Kitamura, Shinya
Yanagi, Teruki
Ujiie, Hideyuki
HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title_full HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title_fullStr HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title_full_unstemmed HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title_short HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses
title_sort her2-targeted antibody–drug conjugates display potent antitumor activities in preclinical extramammary paget’s disease models: in vivo and immunohistochemical analyses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322551/
https://www.ncbi.nlm.nih.gov/pubmed/35884581
http://dx.doi.org/10.3390/cancers14143519
work_keys_str_mv AT tokuchikeiko her2targetedantibodydrugconjugatesdisplaypotentantitumoractivitiesinpreclinicalextramammarypagetsdiseasemodelsinvivoandimmunohistochemicalanalyses
AT maedatakuya her2targetedantibodydrugconjugatesdisplaypotentantitumoractivitiesinpreclinicalextramammarypagetsdiseasemodelsinvivoandimmunohistochemicalanalyses
AT kitamurashinya her2targetedantibodydrugconjugatesdisplaypotentantitumoractivitiesinpreclinicalextramammarypagetsdiseasemodelsinvivoandimmunohistochemicalanalyses
AT yanagiteruki her2targetedantibodydrugconjugatesdisplaypotentantitumoractivitiesinpreclinicalextramammarypagetsdiseasemodelsinvivoandimmunohistochemicalanalyses
AT ujiiehideyuki her2targetedantibodydrugconjugatesdisplaypotentantitumoractivitiesinpreclinicalextramammarypagetsdiseasemodelsinvivoandimmunohistochemicalanalyses