Pediatric glioblastoma - unlike normal cells - are sensitive to the combination of vorinostat and olaparib and to its downstream effector - phosphorylated eIF2α

Abstract

Current therapies offer only a short relief for patients with pediatric glioblastoma (PED-GBM). Therefore, expanding treatment options for this fatal disease is of utmost importance. We found that PED-GBM cell lines, originated from diffuse intrinsic pontine glioma expressing H3K27M mutation (DIPG), or from hemispheric glioma expressing H3G34R mutation, are sensitive to combinations of histone deacetylase and PARP-1 inhibitors (vorinostat with either olaparib or veliparib). These combinations led to an enhanced decrease in their survival, and to increased phosphorylation of eIF2. Experiments with the S51D phosphomimetic variant of eIF2 and with brain-penetrating inhibitors of phosphorylated eIF2 (p-eIF2) dephospohrylation, salubrinal and raphin1, showed that increased eIF2 phosphorylation diminished PED-GBM cell survival and sensitized them to PARP-1 inhibitors as well as to ionizing irradiation, which is the main treatment modality in these patients. PED-GBM cells were also remarkably more sensitive to combination of vorinostat and PARP-1 inhibitors and to salubrinal and raphin1 than normal human astrocytes and fibroblasts. Importantly, although the overall effect of increased eIF2 phosphorylation was a reduced survival of PED-GBM cells, it also increased the cellular level of MTH1, an enzyme that protects treated cells against the incorporation of oxidized nucleotides into nucleic acids, resulting in an enhanced decrease in cell survival in response to the combination of salubrinal and MTH1 inhibitor, TH588. Our results indicate that combinations of the FDA approved drugs, vorinostat and either veliparib or olaparib, could potentially be included in PED-GBM treatment protocols and that the effect of salubrinal and raphin1 on PED-GBM survival warrants further evaluation.