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July 17th, 2025
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Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden
cancer biology
biorxiv

Phenotypic Screening Identifies Flunarizine as an Inhibitor of Radiotherapy-Induced Astrocyte Reactivity with Therapeutic Potential in Glioblastoma

Jeannot, P.Open in Google Scholar•Rosberg, R.Open in Google Scholar•Lindgren, D.Open in Google Scholar•Dawson, J. C.Open in Google Scholar•Pracucci, E.Open in Google Scholar•Borjesson-Freitag, C.Open in Google Scholar•Martinez, J.Open in Google Scholar•Pantazopoulou, V.Open in Google Scholar•Malmberg, M.Open in Google Scholar•Smolag, K. I.Open in Google Scholaret al.

Radiotherapy is part of the standard-of-care for glioblastoma, yet tumors invariably recur as incurable lesions post-treatment. Recent studies suggest that radiation-induced astrocyte reactivity fosters a tumor-supportive environment, however effective strategies targeting reactive astrocyte phenotypes are lacking. Using a novel image-based assay, we screened over 1,700 small molecule compounds, identifying 29 that inhibit radiation-induced astrocyte reactivity in human astrocytes. Among these, Flunarizine, a calcium-entry blocker approved for migraine treatment, significantly reduced astrocyte reactivity in vitro and in vivo. In a genetically engineered glioblastoma mouse model, combining Flunarizine with radiotherapy markedly improved survival without affecting unirradiated controls, indicating specificity for a radiation-induced phenotype. Mechanistically, Flunarizine inhibited radiation-induced fibrosis in vivo and directly suppressed astrocytic TGF-beta activation in vitro. Notably, Flunarizine treatment had no direct effect on primary glioblastoma cells, emphasizing its microenvironmental specificity. In conclusion, we identified Flunarizine as a promising repurposed compound capable of effectively mitigating radiation-induced astrocyte reactivity and delaying glioblastoma recurrence. This approach offers a viable therapeutic strategy to enhance current glioblastoma treatments.

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