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Sci Rep. 2018 Apr 3;8(1):5437. doi: 10.1038/s41598-018-23609-7.

Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma.

Author information

1
Eaton-Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, 02114, USA.
2
Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, MA, 02115, USA.
3
Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, 02115, USA.
4
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
5
Department of Otolaryngology, Harvard Medical School, Boston, MA, 02114, USA.
6
Department of Otolaryngology, Vienna General Hospital, Medical University of Vienna, Vienna, 1090, Austria.
7
Center for Experimental Drugs and Diagnostics, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
8
Eaton-Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, 02114, USA. konstantina_stankovic@meei.harvard.edu.
9
Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, MA, 02115, USA. konstantina_stankovic@meei.harvard.edu.
10
Department of Otolaryngology, Harvard Medical School, Boston, MA, 02114, USA. konstantina_stankovic@meei.harvard.edu.

Abstract

The computational repositioning of existing drugs represents an appealing avenue for identifying effective compounds to treat diseases with no FDA-approved pharmacotherapies. Here we present the largest meta-analysis to date of differential gene expression in human vestibular schwannoma (VS), a debilitating intracranial tumor, and use these data to inform the first application of algorithm-based drug repositioning for this tumor class. We apply an open-source computational drug repositioning platform to gene expression data from 80 patient tumors and identify eight promising FDA-approved drugs with potential for repurposing in VS. Of these eight, mifepristone, a progesterone and glucocorticoid receptor antagonist, consistently and adversely affects the morphology, metabolic activity, and proliferation of primary human VS cells and HEI-193 human schwannoma cells. Mifepristone treatment reduces VS cell viability more significantly than cells derived from patient meningiomas, while healthy human Schwann cells remain unaffected. Our data recommend a Phase II clinical trial of mifepristone in VS.

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