New drug candidates for treatment of atypical meningiomas: An integrated approach using gene expression signatures for drug repurposing

BACKGROUND: Atypical meningiomas are common central nervous system neoplasms with high recurrence rate and poorer prognosis compared to their grade I counterparts. Surgical excision and radiotherapy remains the mainstay therapy but medical treatments are limited. We explore new drug candidates using computational drug repurposing based on the gene expression signature of atypical meningioma tissue with subsequent analysis of drug-generated expression profiles. We further explore possible mechanisms of action for the identified drug candidates using ingenuity pathway analysis (IPA). METHODS: We extracted gene expression profiles for atypical meningiomas (12 samples) and normal meningeal tissue (4 samples) from the Gene Expression Omnibus, which were then used to generate a gene signature comprising of 281 differentially expressed genes. Drug candidates were explored using both the Board Institute Connectivity Map (cmap) and Library of Integrated Network-Based Cellular Signatures (LINCS). Functional analysis of significant differential gene expression for drug candidates was performed with IPA. RESULTS: Using our integrated approach, we identified multiple, already licensed, drug candidates such as emetine, verteporfin, phenoxybenzamine and trazodone. Analysis with IPA revealed that these drugs target signal cascades potentially relevant in pathogenesis of meningiomas, particular examples are the effect on ERK by trazodone, MAP kinases by emetine, and YAP-1 protein by verteporfin. CONCLUSION: Gene expression profiling and use of drug expression profiles have yielded several plausible drug candidates for treating atypical meningioma, some of which have already been suggested by preceding studies. Although our analyses suggested multiple anti-tumour mechanisms for these drugs, further in vivo studies are required for validation. IMPORTANCE OF THE STUDY: To our knowledge this is the first study which combines relatively new, yet established computational techniques to identify additional treatments for a difficult to manage cerebral neoplasm. Beyond proposing already approved drug candidates in the management of atypical meningioma the study highlights the promise held by computational techniques in improving our management strategies.