From GWAS to drug screening: repurposing antipsychotics for glioblastoma

Journal of Translational Medicine

Wei-Zhi Lin¹  Chia-Yang Shiau²  Chi-Ming Chu³  Chi-Tun Tang⁴  Gwo-Jang Wu⁵  Yen-Chun Liu⁶  Yu-Tien Chang⁷  Meng-Chang Lee⁷ 

[1] Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;Fidelity Regulation Therapeutics Inc., 161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;School of Public Health, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan;Department of Neurological Surgery, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Rd., Neihu District, 11490, Taipei, Taiwan;Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan;Department of Obstetrics and Gynecology, Tri-Service General Hospital, No. 325, Sec. 2, Chenggong Rd., Neihu District, 11490, Taipei, Taiwan;School of Medicine, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;School of Public Health, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., 11490, Taipei City, Taiwan;

关键词: Glioblastoma;    In-silico screening;    Drug repositioning;    Antipsychotics;    Antitumor;   

DOI  :  10.1186/s12967-021-03209-2

来源: Springer

【 摘 要 】

BackgroundGlioblastoma 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.MethodsWe investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a ‘pathway/gene-set analysis’ approach.ResultsThe 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.ConclusionIn 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.

【 授权许可】

CC BY