TRTH-19. PRECLINICAL ANALYSIS OF SODIUM VALPROATE FOR THE TREATMENT OF DIPG BY CONVECTION ENHANCED DELIVERY

There is a significant need to develop new treatment strategies to improve the prognosis of DIPG patients. We have previously shown that the HDAC inhibitor, sodium valproate (VPA), reduces the viability of DIPG cells in vitro. Whilst, VPA does cross the blood brain barrier, only 15% of serum concentrations reach the brain, therefore systemic delivery of VPA is unlikely to have significant anti-glioma effects without first incurring dose-limiting systemic toxicities. Convection enhanced delivery (CED) affords the direct administration of drugs to the tumour site, circumventing problems associated with central nervous system penetration of systemically administered drugs. Live/Dead assays were used to assess the effect of VPA on DIPG cell viability after 72 hours and sequential 6 hour drug exposures. In vitro neurotoxicity was determined by exposing normal hippocampal cells to VPA for 6 hours. To determine the feasibility of direct delivery to the brain, VPA was administered by CED to the brain of juvenile wistar rats. Toxicity was assessed by clinical and neuropathological examination of infused brain 21 days after treatment. In addition clearance and stability was analysed by LC-MS/MS. Results to date, demonstrate that VPA reduces cell viability in all DIPG cell lines tested. No significant differences were seen in cellular morphology and network of normal hippocampal derived glio-neuronal cultures in vitro. This was further substantiated by in vivo analysis of toxicity following acute VPA infusion by CED, showing minimal effect on neuronal and glial markers in normal brain. Mass spectrometric analysis determined VPA to be stable in artificial CSF and the half-life in rat brain to be two hours. This data suggests that VPA can feasibly be administered by CED to rat and supports further investigation into the in vivo efficacy of VPA and translation to the clinic.