The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma
Menée à l'aide de modèles murins de glioblastome, cette étude met en évidence l'intérêt de la trifluopérazine, un antagoniste du récepteur de la dopamine, pour prévenir la conversion phénotypique radio-induite des cellules cancéreuses et améliorer la survie
GBM is the most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 mo. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood−brain barrier (BBB). Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the BBB, which prevents phenotype conversion of glioma cells into glioma-initiating cells and prolongs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).
Proceedings of the National Academy of Sciences , résumé, 2019