Ependymoma (EPN) is the third most common paediatric cancer of the central nervous system. Genetic and epigenetic analyses have led to the identification of nine molecular subgroups. Very few chemotherapies demonstrate clinically efficacy against EPN. A recent preclinical study identified gemcitabine (GEM) as a potentially effective agent which is currently in clinical trial. Of note, aberrant DNA methylation has been shown to be an important mechanism for transcriptional inactivation of tumor suppressor genes in pediatric high-grade gliomas including EPN. Aim: To test the efficacy of a DNA methyltransferase inhibitor, decitabine (DEC) alone and in combination with GEM using a preclinical model of high-risk subgroup EPN. Methodology: Female NRG mice were implanted with IC-1425EPN cells into the cortex. The treatment schedule was four consecutive days of DEC (0.2 mg/kg) followed by one day of GEM (60 mg/kg) each week. Tumour progression and treatment response was assessed by weekly bioluminescence imaging. Complete blood counts were analyzed to asses toxicity. Mice were euthanized upon the development of tumour-related morbidity or other ill-health. Kaplan-Meier survival analyses were performed using GraphPad Prism Software. Results: Mice treated with chemotherapies demonstrated a modest increase in survival compared to vehicle-treated controls. No significant difference was observed between mice treated with DEC, GEM or the combination of both. Combination therapy induced neutropenia and prevented the continuation of treatment beyond 4 weeks. Conclusion: Consistent with clinical data, RELA-positive ependymoma is highly resistant to chemotherapy. We showed a mild benefit in survival using DEC or GEM. Current studies are focused on optimizing dosage schedules for these compounds to minimize toxicity and improve efficacy. RNAseq and immunohistopathology are also being used to reveal molecular targets of DEC to potentially unveil additional opportunities for improving therapy for EPN.
Financial Support: The Sao Paulo Research Foundation (FAPESP).