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Preclinical drug screen identifies WEE1 inhibitor and vinca alkaloid as a combination treatment concept for Li-Fraumeni syndrome medulloblastoma

Li-Fraumeni syndrome (LFS) is characterized by constitutional pathogenic TP53 mutation and increased risk of cancer development, including Sonic Hedgehog-activated medulloblastoma (SHH-MB). In LFS patients, radiation and DNA-damaging agents can exhibit lower efficiency and cause secondary malignanci...

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Main Authors: Kolodziejczak, Anna S. (Author) , Selt, Florian (Author) , Peterziel, Heike (Author) , Jamaladdin, Nora (Author) , Mack, Norman (Author) , Maaß, Kendra K. (Author) , Meulenbroeks, Chris (Author) , Sigaud, Romain (Author) , Herold-Mende, Christel (Author) , El Damaty, Ahmed (Author) , Burhenne, Jürgen (Author) , Ohmura, Shunya (Author) , Holland-Letz, Tim (Author) , Kutscher, Lena (Author) , Ernst, Aurélie (Author) , Wei, Pei-Chi (Author) , Grünewald, Thomas G. P. (Author) , Oehme, Ina (Author) , Kool, Marcel (Author) , Jones, David T. W. (Author) , Pajtler, Kristian Wilfried (Author) , Kratz, Christian P. (Author) , Pfister, Stefan (Author) , Witt, Olaf (Author) , Milde, Till (Author)
Format: Article (Journal)
Language:English
Published: 20 February 2026
In: iScience
Year: 2026, Volume: 29, Issue: 2, Pages: 1-20
ISSN:2589-0042
DOI:10.1016/j.isci.2025.114564
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.isci.2025.114564
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2589004225028251
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Author Notes:Anna S. Kolodziejczak, Florian Selt, Heike Peterziel, Nora Jamaladdin, Norman Mack, Kendra Maaß, Chris Meulenbroeks, Romain Sigaud, Christel Herold-Mende, Ahmed El Damaty, Jürgen Burhenne, Shunya Ohmura, Tim Holland-Letz, Lena M. Kutscher, Aurélie Ernst, Pei-Chi Wei, Thomas G.P. Grünewald, Ina Oehme, Marcel Kool, David T.W. Jones, Kristian W. Pajtler, Christian P. Kratz, Stefan M. Pfister, Olaf Witt, and Till Milde
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Summary:Li-Fraumeni syndrome (LFS) is characterized by constitutional pathogenic TP53 mutation and increased risk of cancer development, including Sonic Hedgehog-activated medulloblastoma (SHH-MB). In LFS patients, radiation and DNA-damaging agents can exhibit lower efficiency and cause secondary malignancies. To identify efficacious, safe chemotherapeutic approaches for LFS-associated SHH-MB, 333 compounds were screened in in vitro TP53mut brain tumor cell lines. The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Low genotoxicity of these compounds was determined in vitro in LFS fibroblasts, and in vivo in the LFS mouse model. Despite the drugs’ limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.
Item Description:Online verfügbar 29 December 2025, Version des Artikels 12 January 2026
Gesehen am 15.04.2026
Physical Description:Online Resource
ISSN:2589-0042
DOI:10.1016/j.isci.2025.114564

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