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000308890 1001_ $$0P:(DE-He78)ddb694df5af50ee901e1cd004aa64bfc$$aKolodziejczak, Anna$$b0$$eFirst author$$udkfz
000308890 245__ $$aPreclinical drug screen identifies WEE1 inhibitor and vinca alkaloid as a combination treatment concept for Li-Fraumeni syndrome medulloblastoma.
000308890 260__ $$aSt. Louis$$bElsevier$$c2026
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000308890 520__ $$aLi-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.
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000308890 650_7 $$2Other$$aBiological sciences
000308890 650_7 $$2Other$$aCancer systems biology
000308890 650_7 $$2Other$$aNatural sciences
000308890 650_7 $$2Other$$aPharmacology
000308890 650_7 $$2Other$$aSystems biology
000308890 7001_ $$0P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e$$aSelt, Florian$$b1$$udkfz
000308890 7001_ $$0P:(DE-He78)2727b5cb63b52d0137d4f4e8f110ee7e$$aPeterziel, Heike$$b2$$udkfz
000308890 7001_ $$0P:(DE-He78)16cab27e6475f99246d8555ea5214cb7$$aJamaladdin, Nora$$b3
000308890 7001_ $$0P:(DE-He78)e73a0a4fab40344d89d693cbe1df3109$$aMack, Norman$$b4$$udkfz
000308890 7001_ $$0P:(DE-He78)5100059e746b377e2e0a37c0e24f6bf7$$aMaaß, Kendra$$b5$$udkfz
000308890 7001_ $$aMeulenbroeks, Chris$$b6
000308890 7001_ $$0P:(DE-He78)a5e60710c7515b3e1de74ced6928a9dd$$aSigaud, Romain$$b7
000308890 7001_ $$aHerold-Mende, Christel$$b8
000308890 7001_ $$aEl Damaty, Ahmed$$b9
000308890 7001_ $$aBurhenne, Jürgen$$b10
000308890 7001_ $$0P:(DE-He78)c25b54b0c834093d1f884d2615e305d6$$aOhmura, Shunya$$b11$$udkfz
000308890 7001_ $$0P:(DE-He78)457c042884c901eb0a02c18bb1d30103$$aHolland-Letz, Tim$$b12$$udkfz
000308890 7001_ $$0P:(DE-He78)a56d7a8e916d458441b5ac9484d73c5d$$aKutscher, Lena M$$b13$$udkfz
000308890 7001_ $$0P:(DE-He78)509fb81813c1911954da583129e8ea57$$aErnst, Aurélie$$b14$$udkfz
000308890 7001_ $$0P:(DE-He78)56a961d57d7839fc2d2ebb60c575d9c4$$aWei, Pei-Chi$$b15$$udkfz
000308890 7001_ $$0P:(DE-He78)7a590ab95c6f7ba52880452da78ecd6c$$aGrünewald, Thomas G P$$b16$$udkfz
000308890 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b17$$udkfz
000308890 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b18$$udkfz
000308890 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b19$$udkfz
000308890 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian W$$b20$$udkfz
000308890 7001_ $$aKratz, Christian P$$b21
000308890 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b22$$udkfz
000308890 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b23$$udkfz
000308890 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b24$$eLast author$$udkfz
000308890 773__ $$0PERI:(DE-600)2927064-9$$a10.1016/j.isci.2025.114564$$gVol. 29, no. 2, p. 114564 -$$n2$$p114564$$tiScience$$v29$$x2589-0042$$y2026
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