Abstracts iv7
NEURO-ONCOLOGY • OCTOBER 2016at D9, p=0.05 at D12), whereas the other antibodies did not slow down tumor growth significantly. If combined with radiotherapy, anti-VEGF-A showed no variations to the control arm. Unexpectedly, the combination of radiotherapy with anti-Ang-2/VEGF-A (p=0.01 at D15), and even more with anti-Ang-2 (p=0.04 at D9, p= 0.008 at D12, p=0.003 at D15) lead to an increased tumor diameter.In conclusion, vascular normalization was most effectively achieved by dual targeting of Ang-2 and VEGF-A, which resulted in improved response to chemotherapy, but attenuated effectiveness of radiotherapy. These findings are important for the development of novel antiangiogenic strategies, and planning of future clinical trials in glioblastoma. INTRODUCTION: High-grade gliomas (HGGs) is divided into 3 major subtypes based on core gene signatures; mesenchymal (MES), proneural (PN) and proliferative. Among them, HGGs profiled in the MES subtype tend to show worse prognosis than others. Recently, also as for glioma stem cells, two mutually exclusive subtypes with distinct dysregulated signaling and metabolic pathways has been identified; MES-GSC and PN-GSC. It is known that MES-GSC displays more aggressive phenotypes and is markedly resistant to radiation as compared with PN-GSC. Delta-aminolevurinic acid (ALA) is the first metabolite in the porphyrin synthesis and the exogenous administration of ALA increased the endogenous production of photosensitizer protoporphyrin-IX (PpIX) in HGG tumor cells. Recently, several reports have revealed that ALA has an ability to enhance the therapeutic efficacy of X-ray radiotherapy (XRT) for various malignant tumors in vitro and in vivo. The aim of the present study is to investigate whether ALA can decrease the radioresistance of GSCs.MATERIAL & METHODS: We used 3 MES-GSCs and 2 PN-GSCs established from surgical specimens of human malignant gliomas. We defined the above GSCs cultured in an adherent condition with FBS and without glutamine for more than 2 weeks as glioma "differentiated" cells (GDCs). Firstly, we quantified the intracellular PpIX in the GSCs and their corresponding GDCs by FACS and LC. Then, we assessed the in vitro therapeutic effect of ALA-XRT on them; MTT-assay, sphere-or colony-forming assay, and apoptosis assay were performed. We made an intracerebral glioma model using one MES-GSC to evaluate in vivo therapeutic effect of ALA-XRT; MES-GSC transplanted mice were randomly divided into 4 groups, ALA-XRT, XRT only, ALA only and control. Total 30 Gy in 3 Gy fractions of X-ray was irradiated to the mice in 1st and 2nd group. The intraperitoneal injection of 240 mg/kg ALA was done 6 hours prior to each irradiation for the mice in 1st and 3rd group. RESULTS: 1) All MES-GSCs showed significantly higher PpIX accumulation than their corresponding MES-GDCs. Meanwhile, two PN-GSCs showed lower intracellular PpIX level than their corresponding PN-GDCs. 2) All MES-GSCs showed higher resistance to X-ray than their corresponding MES-GDCs, but the radioresi...