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High-throughput neural stem cell-based drug screening identifies S6K1 inhibition as a selective vulnerability in sonic hedgehog-medulloblastoma.

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posted on 2025-01-22, 09:56 authored by Leilei Zhou, Niek Van BreeNiek Van Bree, Lola Boutin, Jinhye Ryu, Simon Moussaud, Mingzhi LiuMingzhi Liu, Magdalena Otrocka, Magnus OlssonMagnus Olsson, Anna Falk, Margareta WilhelmMargareta Wilhelm
BACKGROUND: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current treatments have increased overall survival but can lead to devastating side effects and late complications in survivors, emphasizing the need for new, improved targeted therapies that specifically eliminate tumor cells while sparing the normally developing brain. METHODS: Here, we used a sonic hedgehog (SHH)-MB model based on a patient-derived neuroepithelial stem cell system for an unbiased high-throughput screen with a library of 172 compounds with known targets. Compounds were evaluated in both healthy neural stem cells (NSCs) and tumor cells derived from the same patient. Based on the difference of cell viability and drug sensitivity score between normal cells and tumor cells, hit compounds were selected and further validated in vitro and in vivo. RESULTS: We identified PF4708671 (S6K1 inhibitor) as a potential agent that selectively targets SHH-driven MB tumor cells while sparing NSCs and differentiated neurons. Subsequent validation studies confirmed that PF4708671 inhibited the growth of SHH-MB tumor cells both in vitro and in vivo, and that knockdown of S6K1 resulted in reduced tumor formation. CONCLUSIONS: Overall, our results suggest that inhibition of S6K1 specifically affects tumor growth, whereas it has less effect on non-tumor cells. Our data also show that the NES cell platform can be used to identify potentially effective new therapies and targets for SHH-MB.

Funding

Identifying molecular mechanisms and therapeutic targets in childhood neural tumors : Swedish Research Council | 2020-01427_VR

Identifying molecular mechanisms and therapeutic targets in childhood neural tumors : Swedish Research Council | 2023-02206_VR

Reprogrammed patient stem cells as a model for the development of childhood cancer : Barncancerfonden | PR2021-0080

History

File version

  • Published

Publication status

Published

Sub type

Article

Journal

Neuro-Oncology

ISSN

1522-8517

eISSN

1523-5866

Volume

26

Issue

9

Pagination

1685-1699

Language

  • eng

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