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Background
Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM.
Methods
mRNA expression data of patient-derived GBM (n = 1,279) and normal brain tissue (n = 46) samples were collected from GEO and TCGA. Functional genomic mRNA (FGmRNA) profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on 1) known interactions with anti-neoplastic drugs, 2) current drug development status in humans, and 3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo.
Results
We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interactions with antineoplastic agents. 17 out of the 27 genes, including EGFR and VEGFA, have been clinically evaluated in GBM with limited efficacy. For the remaining ten genes, RRM2, MAPK9 (JNK2, SAPK1a), and XIAP play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth.
Conclusions
The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
Glioblastoma (GBM) is an incurable cancer type. New therapeutic options are investigated, including targeting the mitogen-activated protein kinase (MAPK) pathway using MEK-inhibitors as radiosensitizers.In this study, we investigated whether MEK-inhibition via PD0325901 leads to radiosensitization in experimental in vitro and in vivo models of GBM. In vitro, GBM8 multicellular spheroids were irradiated with 3 fractions of 2 Gy, during 5 consecutive days of incubation with either PD0325901 or MEK-162.Regrowth and viability of spheroids monitored until day 18, showed that both MEK-inhibitors had an in vitro radiosensitizing effect. In vivo, PD0325901 concentrations were relatively constant throughout multiple brain areas. We combined PD0325901 with radiotherapy in the GBM8 orthotopic mouse model.Tumor growth was measured weekly by bioluminescence imaging and overall survival and toxicity were assessed, showing temporal PD0325901-related adverse events such as dermatitis in 4 out of 14 mice (29%). Mice that were treated with radiation alone or combined with PD0325901 had signi cantly better survival compared to vehicle (both P<0.005), however, no signi cant interaction between PD0325901 MEK-inhibition and irradiation was observed. The difference between the radiotherapy-enhancing effect of PD0325901 in vitro and in vivo urges further pharmacodynamic/pharmacokinetic investigation of PD0325901 and possibly other candidate MEK inhibitors.
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