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Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma

Radke, Katarzyna LU ; Aaltonen, Kristina LU orcid ; Muciño-Olmos, Erick A LU orcid ; Esfandyari, Javanshir LU ; Adamska, Aleksandra LU ; Siaw, Joachim T LU orcid ; Adamic, Dora LU orcid ; Lago, Chiara LU ; Mañas, Adriana LU and Seger, Alexandra LU orcid , et al. (2025) In EMBO Molecular Medicine
Abstract

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol... (More)

Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change toward an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
EMBO Molecular Medicine
publisher
Wiley-Blackwell
external identifiers
  • pmid:41437160
ISSN
1757-4684
DOI
10.1038/s44321-025-00349-6
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
1dfa6776-82cd-4d34-b29b-ae3b1a302c2b
date added to LUP
2025-12-30 08:36:38
date last changed
2026-01-08 09:42:00
@article{1dfa6776-82cd-4d34-b29b-ae3b1a302c2b,
  abstract     = {{<p>Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change toward an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.</p>}},
  author       = {{Radke, Katarzyna and Aaltonen, Kristina and Muciño-Olmos, Erick A and Esfandyari, Javanshir and Adamska, Aleksandra and Siaw, Joachim T and Adamic, Dora and Lago, Chiara and Mañas, Adriana and Seger, Alexandra and Hansson, Karin and Rogova, Oksana and Lehn, Sophie and Mason, Daniel J and O'Donovan, Daniel J and Roberts, Ian and Lock, Antonia and Brennan, Jane and Pietras, Kristian and Davies, Emma J and Spégel, Peter and Bedoya-Reina, Oscar C and Brown, David and Thompson, Neil T and Spadoni, Cesare and Bexell, Daniel}},
  issn         = {{1757-4684}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{Repurposing statins and phenothiazines to treat chemoresistant neuroblastoma}},
  url          = {{http://dx.doi.org/10.1038/s44321-025-00349-6}},
  doi          = {{10.1038/s44321-025-00349-6}},
  year         = {{2025}},
}