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Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors

Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involve...

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Autores principales: Tao, Ting, Shi, Hui, Wang, Meng, Perez-Atayde, Antonio R., London, Wendy B., Gutierrez, Alejandro, Lemos, Bernardo, Durbin, Adam D., Look, A. Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537400/
https://www.ncbi.nlm.nih.gov/pubmed/32728700
http://dx.doi.org/10.1084/jem.20191871
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author Tao, Ting
Shi, Hui
Wang, Meng
Perez-Atayde, Antonio R.
London, Wendy B.
Gutierrez, Alejandro
Lemos, Bernardo
Durbin, Adam D.
Look, A. Thomas
author_facet Tao, Ting
Shi, Hui
Wang, Meng
Perez-Atayde, Antonio R.
London, Wendy B.
Gutierrez, Alejandro
Lemos, Bernardo
Durbin, Adam D.
Look, A. Thomas
author_sort Tao, Ting
collection PubMed
description Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT–mTOR–S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.
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spelling pubmed-75374002021-04-05 Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors Tao, Ting Shi, Hui Wang, Meng Perez-Atayde, Antonio R. London, Wendy B. Gutierrez, Alejandro Lemos, Bernardo Durbin, Adam D. Look, A. Thomas J Exp Med Brief Definitive Report Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT–mTOR–S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity. Rockefeller University Press 2020-07-29 /pmc/articles/PMC7537400/ /pubmed/32728700 http://dx.doi.org/10.1084/jem.20191871 Text en © 2020 Tao et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Tao, Ting
Shi, Hui
Wang, Meng
Perez-Atayde, Antonio R.
London, Wendy B.
Gutierrez, Alejandro
Lemos, Bernardo
Durbin, Adam D.
Look, A. Thomas
Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title_full Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title_fullStr Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title_full_unstemmed Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title_short Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
title_sort ganglioneuromas are driven by activated akt and can be therapeutically targeted with mtor inhibitors
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537400/
https://www.ncbi.nlm.nih.gov/pubmed/32728700
http://dx.doi.org/10.1084/jem.20191871
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