Harnessing miR-138 Modulating Agents to Combat Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme (GBM) is a highly aggressive brain cancer with less than 5% 5-year survival rate. Due to the heterogeneous permeability of the brain-tumour barrier, current multimodal treatment methods are limited in effectiveness. MicroRNAs are short, non-coding RNAs implicated in cancer. MicroRNA-138 (miR-138) appears upregulated in treatment-resistant glioma stem cells. miR-138 modulating compounds consists of Antisense Oligonucleotide-138 (ASO-138) and cell-penetrating peptide (CPP) conjugated together. To investigate the efficacy of miR-138 modulating compounds at reducing miR-138 levels, GBM cells were cultured then treated with ASO-138/CPP at different concentrations and durations. Cell viability and miR-138 expression were then measured via MTS assay and RT-qPCR respectively. At high concentrations, ASO-138/CPP exhibits low cytotoxicity, demonstrating its biocompatibility with GBM cells. A shorter treatment duration of 24 h is also more effective at downregulating expression of miR-138. The 4 CPPs tested had different properties and exhibited varying efficacies at downregulating expression of miR-138, ranging from no to extremely high statistical significance (p < 0.0001). Thus, to maximise therapeutic outcomes, the right CPP must be chosen and patients should be treated every 24 h for greater reduction in miR-138 levels. For further research, in vivo mouse studies can be utilised to determine systemic toxicity and potential off-target effects. Delivery of ASO-138/CPP through the brain-tumour barrier must also be optimised to translate our in vitro findings into a feasible and effective treatment method. By addressing critical challenges in GBM treatment, this project hopes to demonstrate the potential of miRNA modulating agents in providing effective, novel alternatives for hard-to-treat cancers.