MutT homolog 1 counteracts the effect of anti-neoplastic treatments in adult and pediatric glioblastoma cells.

Glioblastoma, a fatal disease in both adult and pediatric patients, currently has limited treatment options that offer no more than temporary relief. Our experiments with adult and pediatric glioblastoma cell lines showed that radiation induces a dose-dependent increase in the level of MutT homolog 1 (MTH1) - an enzyme that hydrolyzes oxidized purine nucleoside triphosphates. Similarly, the combination of vorinostat, which is a histone deacetylase inhibitor, and ABT-888, which is a PARP-1 inhibitor, enhanced clonogenic death and increased the MTH1 level, relative to each treatment alone. This result suggests that the MTH1 level is directly related to the damage that is inflicted upon the cells, and its activity protects them against anti-neoplastic therapy. Indeed, the MTH1 inhibitor TH588 and MTH1 siRNA increased glioblastoma's response to both radiation and the combination of vorinostat and ABT-888. TH588 also inhibited glioblastoma's capacity for migration and invasion. In normal fibroblasts, low radiation doses and the combination of vorinostat and ABT-888 decreased the level of the enzyme. TH588 did not alter the fibroblasts' response to radiation and only mildly affected their response to the combination of vorinostat and ABT-888. In summary, the inhibition of MTH1 is required to better realize the therapeutic potential of anti-neoplastic treatments in glioblastoma.

Schwannomas exhibit distinct size-dependent gene-expression patterns.

AIM: Neurofibromatosis type 2 (NF2)-associated vestibular schwannomas have variable size at presentation which presents a unique challenge in NF2 patient management. Therefore, we investigated the molecular signature characteristic of the differences in size for improved individualized precise therapy. MATERIALS & METHODS: RNA expression analysis was performed on 15 small and 27 large NF2-associated vestibular schwannoma tumors using a microarray analyzing over 47,000 transcripts. RESULTS: A signature of 11 genes was found to be correlated with NF2 tumor size. CONCLUSION: We have identified the genetic hallmark that differentiates large NF2-associated tumors from smaller tumors. This is the first time that these genes have been shown to be the hallmark for NF2 tumor size.