TRTH-18. COMBINED TOPOTECAN AND CARBOPLATIN THERAPY FOR DIPG SUPPRESSES CELL GROWTH IN VITRO AND IS WELL TOLERATED WHEN DELIVERED BY CONVECTION ENHANCED DELIVERY IN VIVO

Abstract

AbstractDespite clinical advances, diffuse intrinsic pontine glioma (DIPG) remains universally fatal and urgently requires new treatment modalities to improve prognosis. Topotecan and carboplatin have formed treatment regimes for pediatric cancers as single agents with limited success. Both drugs have poor central nervous system penetration which may explain the lack of efficacy in the clinic when delivered systemically, furthermore, as single agents they have been administered to children with DIPG by convection enhanced delivery (CED) in early phase clinical trials and compassionate use programmes. Here, we describe the use of topotecan and carboplatin as combinatorial therapy for the treatment of DIPG in vitro and its tolerance when administered in vivo in a small animal model of intermittent CED. In this study, we assessed the in vitro cytotoxicity of combined topotecan and carboplatin in two ex vivo patient derived DIPG cell lines (SF7761 and SF8628). Combination therapy in vitro showed an additive effect on cell viability when compared to each single agent. Next, we determined the tolerance and toxicity of both drugs administered by CED using an implantable catheter system in juvenile wistar rats by clinical and neuropathological examination of infused brain 21 days after treatment. Results show that topotecan and carboplatin have an enhanced effect on DIPG cell viability in vitro when used in combination. This combination is currently being explored in a wider cohort of DIPG cell lines. In vivo assessment of sequential drug therapy in normal rat brain, shows this combination to be well tolerated and exhibited minimal CNS toxicity. Further work is required to see if this combination is effective in pre-clinical models of DIPG when administered by CED.