EPEN-01. CHARACTERIZATION AND DRUG TESTING IN PRECLINICAL EPENDYMOMA MODELS

摘要

INTRODUCTION: Currently there are no effective chemotherapeutic treatments for ependymomas, with maximal surgical excision and radiotherapy the mainstays of treatment. The identification of at least 9 molecularly distinct subgroups, suggests effective treatments are likely to be subgroup specific and subgroup focused preclinical investigations are urgently needed. However, such investigations have been hampered by the lack of appropriate and models in which to test potential treatments. This study aims to establish such models for the purpose of testing novel subgroup specific drug treatments. METHODS/RESULTS: Ependymoma samples from two patients have been successfully cultured in neurobasal media, with the cells growing both as adherent cultures and neurospheres. Whole genome DNA methylation screening and IHC, categorized the samples as falling within the ST-RELA and PFA subgroups respectively. Drug testing on ST-RELA neurospheres has shown treatment with Bortezomib, in combination with either Vorinostat or Panobinostat, results in significant synergistic benefits, with neurosphere viability reduced to almost zero, using doses that are half the IC50 of each drug. Preliminary analysis suggests the drugs are leading to an increase in apoptosis. Brain slice co-culture models have been successfully established, for the purpose of further drug testing and investigating the effects of the drugs upon normal brain tissue. Cells dissociated from the ST-RELA patient sample and low passage cultures, injected intracranially into NSG mice, resulted in tumour formation in 6 of the 19 mice, with plans underway to test the drug combinations in PDX mouse models. CONCLUSION: In the absence of known driver mutations for 8 of the 9 ependymoma subgroups, the establishment of patient derived preclinical models provides a mechanism for testing novel subgroup specific treatments. The current results suggest that Bortezomib in combination with histone deacetylase inhibitors may be an effective treatment in patients with ST-RELA ependymomas.