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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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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. |
format | Online Article Text |
id | pubmed-7537400 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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