Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma

BackgroundNeuroblastoma (NB) is a childhood cancer with a high relapse rate despite intensive treatment. TRPA1 is a pain-sensing ion channel with downstream impacts on proliferative and pro-apoptotic pathways. Here, we evaluated TRPA1 expression in NB and performed pharmacological inhibition in prec...

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Autores: Seger A, Adamic D, Olmos EM, Nilsson J, Granados-Aparici S, Vieco-Marti I, Esfandyari J, Engström M, Martinez J, Mañas A, Navarro S, Noguera R, Aaltonen K, Bexell D
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p20179
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/20179
Access Level:acceso abierto
Palabra clave:chemotherapy
neuroblastoma
TRPA1
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spelling Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified NeuroblastomaSeger AAdamic DOlmos EMNilsson JGranados-Aparici SVieco-Marti IEsfandyari JEngström MMartinez JMañas ANavarro SNoguera RAaltonen KBexell DchemotherapyneuroblastomaTRPA1BackgroundNeuroblastoma (NB) is a childhood cancer with a high relapse rate despite intensive treatment. TRPA1 is a pain-sensing ion channel with downstream impacts on proliferative and pro-apoptotic pathways. Here, we evaluated TRPA1 expression in NB and performed pharmacological inhibition in preclinical models to assess its potential as a therapeutic target in NB.MethodsTRPA1 protein levels were assessed in NB patient tumors on tissue microarrays. Bulk and single-cell gene expression data were retrieved from publicly available databases. The effects of three TRPA1 inhibitors (AP-18, A967079, and Bay 390) on NB cell viability and cell death were evaluated using NB patient-derived xenograft (PDX)-derived organoids. In vivo testing was performed in a MYCN-amplified NB PDX model. Drug combination testing was performed using combination or sequential treatments and evaluated using drug synergy scores.ResultsTRPA1 is widely expressed in NB patient tumors and preclinical patient-derived NB models. Pharmacological TRPA1 inhibition decreased NB cell viability and increased cell death. In vivo TRPA1 inhibition alone did not significantly affect NB tumor growth. Pretreatment with TRPA1 inhibition prior to chemotherapy resulted in synergistic effects in vitro.ConclusionsTRPA1 is expressed in NB tumors, and pharmacological TRPA1 inhibition can be effective in vitro and synergistic when used as pretreatment to chemotherapy. However, the tested inhibitors did not show in vivo efficacy, at least as monotherapy.WILEY2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/20179PEDIATRIC BLOOD & CANCERISSN: 15455009ISSNe: 15455017reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p201792026-06-07T16:35:31Z
dc.title.none.fl_str_mv Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
title Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
spellingShingle Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
Seger A
chemotherapy
neuroblastoma
TRPA1
title_short Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
title_full Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
title_fullStr Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
title_full_unstemmed Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
title_sort Evaluation of TRPA1 as a Therapeutic Target in MYCN-Amplified Neuroblastoma
dc.creator.none.fl_str_mv Seger A
Adamic D
Olmos EM
Nilsson J
Granados-Aparici S
Vieco-Marti I
Esfandyari J
Engström M
Martinez J
Mañas A
Navarro S
Noguera R
Aaltonen K
Bexell D
author Seger A
author_facet Seger A
Adamic D
Olmos EM
Nilsson J
Granados-Aparici S
Vieco-Marti I
Esfandyari J
Engström M
Martinez J
Mañas A
Navarro S
Noguera R
Aaltonen K
Bexell D
author_role author
author2 Adamic D
Olmos EM
Nilsson J
Granados-Aparici S
Vieco-Marti I
Esfandyari J
Engström M
Martinez J
Mañas A
Navarro S
Noguera R
Aaltonen K
Bexell D
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv chemotherapy
neuroblastoma
TRPA1
topic chemotherapy
neuroblastoma
TRPA1
description BackgroundNeuroblastoma (NB) is a childhood cancer with a high relapse rate despite intensive treatment. TRPA1 is a pain-sensing ion channel with downstream impacts on proliferative and pro-apoptotic pathways. Here, we evaluated TRPA1 expression in NB and performed pharmacological inhibition in preclinical models to assess its potential as a therapeutic target in NB.MethodsTRPA1 protein levels were assessed in NB patient tumors on tissue microarrays. Bulk and single-cell gene expression data were retrieved from publicly available databases. The effects of three TRPA1 inhibitors (AP-18, A967079, and Bay 390) on NB cell viability and cell death were evaluated using NB patient-derived xenograft (PDX)-derived organoids. In vivo testing was performed in a MYCN-amplified NB PDX model. Drug combination testing was performed using combination or sequential treatments and evaluated using drug synergy scores.ResultsTRPA1 is widely expressed in NB patient tumors and preclinical patient-derived NB models. Pharmacological TRPA1 inhibition decreased NB cell viability and increased cell death. In vivo TRPA1 inhibition alone did not significantly affect NB tumor growth. Pretreatment with TRPA1 inhibition prior to chemotherapy resulted in synergistic effects in vitro.ConclusionsTRPA1 is expressed in NB tumors, and pharmacological TRPA1 inhibition can be effective in vitro and synergistic when used as pretreatment to chemotherapy. However, the tested inhibitors did not show in vivo efficacy, at least as monotherapy.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/20179
url https://incliva.portalinvestigacion.com/publicaciones/20179
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv WILEY
publisher.none.fl_str_mv WILEY
dc.source.none.fl_str_mv PEDIATRIC BLOOD & CANCER
ISSN: 15455009
ISSNe: 15455017
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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