Identification of novel therapeutic targets in glioblastoma with functional genomic mRNA profiling.

Abstract

2018 Background: Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs and has a dismal prognosis. Therefore, there is an unmet need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets by identifying upregulated genes in GBM with known antineoplastic drug interactions. Methods: Publicly available, raw microarray expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we applied functional genomic mRNA profiling (FGmRNA-profiling), a method that is able to correct the gene expression profile of an individual tumor for physiological and experimental factors, which are considered not to be relevant for the observed tumor phenotype. Next, the FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: known interaction with antineoplastic agents and the current status of clinical evaluation in humans. Results: After FGmRNA-profiling 66 normal brain tissue samples and 1280 patient-derived GBM samples, class comparison identified 712 significantly upregulated genes. Of all significantly upregulated genes, 27 genes interacted with antineoplastic drugs. 17 out of these 27 druggable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM, and had limited efficacy. Out of the 10 remaining druggable genes, we prioritized RRM2, MAPK9 and XIAP, as these genes are associated with biologic pathways involved in the carcinogenesis of GBM and are therefore considered as novel potential therapeutic targets. Conclusions: Based on data-driven prioritization, we identified three potential therapeutic druggable targets, which have not yet been explored in the context of glioblastoma. Further preclinical and clinical research on the inhibition of these druggable genes is necessary and may lead to an improvement of treatment outcomes for patients with GBM.