The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

ABSTRACT: Glioblastoma is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and -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 glioblastoma. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in glioblastoma by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146358 | GEO | 2020/03/05

REPOSITORIES: GEO