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Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2020 Oct 05; Vol. 217 (10). - Publication Year :
- 2020
-
Abstract
- 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.<br />Competing Interests: Disclosures: T. Tao reported grants from Pediatric Cancer Research Foundation and grants from Rally Foundation for Childhood Cancer Research and the Open Hands Overflowing Hearts during the conduct of the study. H. Shi reported grants from Alex's Lemonade Stand Foundation during the conduct of the study. A.T. Look reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.<br /> (© 2020 Tao et al.)
- Subjects :
- Animals
Animals, Genetically Modified
Apoptosis
Cell Cycle
Ganglioneuroma drug therapy
Gene Expression Regulation, Neoplastic
Humans
Neuroblastoma drug therapy
Neuroblastoma metabolism
Signal Transduction
TOR Serine-Threonine Kinases metabolism
Zebrafish
Antineoplastic Agents pharmacology
Ganglioneuroma metabolism
Proto-Oncogene Proteins c-akt metabolism
TOR Serine-Threonine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 217
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32728700
- Full Text :
- https://doi.org/10.1084/jem.20191871