From GWAS to drug screening: repurposing antipsychotics for glioblastoma

Abstract

Background: Glioblastoma is currently an incurable cancer. Genome-wide association studies have demonstrated that 41 genetic variants are associated with glioblastoma and may provide an option for drug development.

Methods: We investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a 'pathway/gene-set analysis' approach.

Results: The in-silico screening led to the discovery of 12 candidate drugs. DepMap portal revealed that 42 glioma cell lines show higher sensitivities to 12 candidate drugs than to Temozolomide, the current standard treatment for glioblastoma.

Conclusion: In particular, cell lines showed significantly higher sensitivities to Norcyclobenzaprine and Protriptyline which were predicted to bind targets to disrupt a certain molecular function such as DNA repair, response to hormones, or DNA-templated transcription, and may lead to an effect on survival-related pathways including cell cycle arrest, response to ER stress, glucose transport, and regulation of autophagy. However, it is recommended that their mechanism of action and efficacy are further determined.

Keywords: Antipsychotics; Antitumor; Drug repositioning; Glioblastoma; In-silico screening.

Fig. 1

Experimental design and flow chart for in-silico screening

Fig. 2

Sensitivity of glioma cells to TMZ and candidate drugs. A The sensitivities of glioma cells to candidate drugs and TMZ ranking by mean sensitivity. (Ranking by mean sensitivity. × : mean value. CI: Confidence Interval) (B) Cells show significant higher sensitivities to two of candidate, Norcyclobenzaprine and Protriptyline (P = 5.89E−05 and 3.84E−05 respectively). C, D Heatmap of gene show significantly different expression in sensitive and non-sensitive cells to Norcyclobenzaprine and Protriptyline, respectively. The order of cell line follows the sensitivities of cells to Norcyclobenzaprine and Protriptyline from highest (left) to lowest (right)

Fig. 2

Sensitivity of glioma cells to TMZ and candidate drugs. A The sensitivities of glioma cells to candidate drugs and TMZ ranking by mean sensitivity. (Ranking by mean sensitivity. × : mean value. CI: Confidence Interval) (B) Cells show significant higher sensitivities to two of candidate, Norcyclobenzaprine and Protriptyline (P = 5.89E−05 and 3.84E−05 respectively). C, D Heatmap of gene show significantly different expression in sensitive and non-sensitive cells to Norcyclobenzaprine and Protriptyline, respectively. The order of cell line follows the sensitivities of cells to Norcyclobenzaprine and Protriptyline from highest (left) to lowest (right)