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Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma
SIMPLE SUMMARY: A large percentage of patients with neuroblastoma relapse and die, despite treatment, thus demanding new personalized strategies and therapeutic targets. Hypoxia, a condition of reduced oxygenation in several solid tumors, has profound effects on the neuroblastoma (NB) tumor biology...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200206/ https://www.ncbi.nlm.nih.gov/pubmed/34199959 http://dx.doi.org/10.3390/cancers13112809 |
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author | Uva, Paolo Bosco, Maria Carla Eva, Alessandra Conte, Massimo Garaventa, Alberto Amoroso, Loredana Cangelosi, Davide |
author_facet | Uva, Paolo Bosco, Maria Carla Eva, Alessandra Conte, Massimo Garaventa, Alberto Amoroso, Loredana Cangelosi, Davide |
author_sort | Uva, Paolo |
collection | PubMed |
description | SIMPLE SUMMARY: A large percentage of patients with neuroblastoma relapse and die, despite treatment, thus demanding new personalized strategies and therapeutic targets. Hypoxia, a condition of reduced oxygenation in several solid tumors, has profound effects on the neuroblastoma (NB) tumor biology and patient prognosis. Establishing new connections between hypoxia and pharmacological compounds may provide novel treatment strategies for NB patients. In the present study, we successfully identified 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors, whose anti-hypoxia effect was shown on the gene expression profile of nine distinct cell lines using connectivity map software. We independently confirmed these findings on NB cells cultured under hypoxia conditions and treated with the mTORC inhibitor PP242. PI3K/Akt/mTOR inhibitors represent a potential effective class of compounds targeting hypoxia in neuroblastoma. PI3K/Akt/mTOR inhibitors may thus find future applicability as a new adjuvant therapy in randomized clinical trials involving neuroblastoma patients with hypoxic tumors. ABSTRACT: Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis. |
format | Online Article Text |
id | pubmed-8200206 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82002062021-06-14 Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma Uva, Paolo Bosco, Maria Carla Eva, Alessandra Conte, Massimo Garaventa, Alberto Amoroso, Loredana Cangelosi, Davide Cancers (Basel) Article SIMPLE SUMMARY: A large percentage of patients with neuroblastoma relapse and die, despite treatment, thus demanding new personalized strategies and therapeutic targets. Hypoxia, a condition of reduced oxygenation in several solid tumors, has profound effects on the neuroblastoma (NB) tumor biology and patient prognosis. Establishing new connections between hypoxia and pharmacological compounds may provide novel treatment strategies for NB patients. In the present study, we successfully identified 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors, whose anti-hypoxia effect was shown on the gene expression profile of nine distinct cell lines using connectivity map software. We independently confirmed these findings on NB cells cultured under hypoxia conditions and treated with the mTORC inhibitor PP242. PI3K/Akt/mTOR inhibitors represent a potential effective class of compounds targeting hypoxia in neuroblastoma. PI3K/Akt/mTOR inhibitors may thus find future applicability as a new adjuvant therapy in randomized clinical trials involving neuroblastoma patients with hypoxic tumors. ABSTRACT: Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis. MDPI 2021-06-04 /pmc/articles/PMC8200206/ /pubmed/34199959 http://dx.doi.org/10.3390/cancers13112809 Text en © 2021 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 Uva, Paolo Bosco, Maria Carla Eva, Alessandra Conte, Massimo Garaventa, Alberto Amoroso, Loredana Cangelosi, Davide Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title | Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title_full | Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title_fullStr | Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title_full_unstemmed | Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title_short | Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma |
title_sort | connectivity map analysis indicates pi3k/akt/mtor inhibitors as potential anti-hypoxia drugs in neuroblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200206/ https://www.ncbi.nlm.nih.gov/pubmed/34199959 http://dx.doi.org/10.3390/cancers13112809 |
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