10025- ET-3 IDENTIFICATION OF A NEW MOLECULAR TARGET FOR MESENCHYMAL GLIOBLASTOMA AND ITS FUNCTION

Abstract In order to identify molecular target(s) for treatment of glioblastoma multiforme (GBM), we searched for genes characteristically expressed in mesenchymal (MES)-type GBM and identified HVEM (herpes virus entry mediator, also known as TNF receptor superfamily 14), whose expression is higher in brain tumor tissue than in normal brain, especially in MES-type GBM. Furthermore, a significant correlation between HVEM expression and prognosis of GBM patients was found. Using GBM cells from HGCC (human glioblastoma cell culture) bank, the effect of HVEM was analyzed. Knockdown of HVEM expression in MES-type GBM cells resulted in a significant reduction in proliferative and sphere-forming capacity in vitro and loss of stem cell-like characteristics was observed. In an intracranial transplantation study in nude mice, tumor-forming capacity was also inhibited in MES-type GBM cells in which HVEM expression was knocked down, and mouse survival was significantly prolonged. For targeting HVEM, we generated alpaca-derived anti-human HVEM VHH (variable domain of heavy chain of heavy chain antibody) antibody, and analyzed the effects of the VHH antibody on MES-type GBM cells in vitro and in vivo. Currently, we are conducting preclinical studies using the VHH antibody targeting human HVEM and promoting research for future clinical application of human HVEM antibodies to MES-type GBM (This work has been conducted in collaboration with Drs. Carl-Henrik Heldin and Bengt Westermark, Uppsala University, Sweden).