The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma

• DOI: 10.1073/pnas.1920154117
• Publication Date: 2020-05-02T00:06:32Z
• Authors: Kruttika Bhat; Mohammad Saki; Erina Vlashi; Fei Cheng; Sara Duhachek-Muggy; Claudia Alli; Garrett Yu; Paul Medina; Ling He; Robert Damoiseaux; Matteo Pellegrini; Nathan R. Zemke; Phioanh Leia Nghi...; Timothy F. Cloughesy; Linda M. Liau; Harley I. Kornblum; Frank Pajonk
• Keywords: 0301 basic medicine; Dopamine; Messenger; Mice, SCID; Inbred C57BL; Radiation Tolerance; Receptors, Dopamine; Glycogen Synthase Kinase 3; Mice; Stem Cell Research - Nonembryonic - Human; Mice, Inbred NOD; Receptors; beta Catenin; Cancer; Brain Neoplasms; Glioma; Trifluoperazine; 3. Good health; Gene Expression Regulation, Neoplastic; Phenotype; 5.1 Pharmaceuticals; glioma-initiating cells; Oncology and Carcinogenesis; 610; SCID; 03 medical and health sciences; Rare Diseases; 616; Genetics; Animals; RNA, Messenger; dopamine receptor antagonist; Neoplastic; Biomedical and Clinical Sciences; Animal; Prevention; SOXB1 Transcription Factors; dedifferentiation; Neurosciences; glioblastoma; Stem Cell Research; Xenograft Model Antitumor Assays; Brain Disorders; Brain Cancer; radiation; Mice, Inbred C57BL; Disease Models, Animal; Orphan Drug; Gene Expression Regulation; Disease Models; Radiation Oncology; Inbred NOD; RNA; Dopamine Antagonists; Glioblastoma

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).