The brain penetrating pan EPH receptor antagonist, UNIPR1331, shows potent antiangiogenic and anti-invasive effects in glioblastoma preclinical models

BACKGROUND. Angiogenesis is often deregulated and exploited in tumor growth. After initial responses to anti-VEGF/VEGFR compounds, glioblastomas (GBM) tend to grow back in a more invasive manner and relapse. Here we tested UniPr1331, a novel brain penetrating pan Eph receptor antagonist, in combination with bevacizumab or sunitinib. METHODS: The effects of bevacizumab, sunitinib and UniPR1331, were tested alone or in combination in subcutaneous xenografts of U87MG, U251 and T98G cells as well as on intra-cranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. RESULTS: UniPr1331 reduces the in vitro migratory and invasive capacities of GBM and endothelial cells as well as vasculomimicry in U87MG cells at doses which were not able to modify cell proliferation. Reduction of the tube formation of endothelial cells was observed in vitro and in chick embryo chorioallantoic membrane model. UniPr1331 was tested in orthotopic intra-brain tumors by using luciferase-taggeted U87MG and TPC8 cells. We observed that UniPr1331 inhibited the tumor growth of GBM cell models and was additive/synergistic with s bevacizumab or sunitinib increasing significantly Disease Free Survival and Overall Survival. Our data indicate that UniPR13l may represent a novel therapeutic strategy to tackle GBM tumors increasing and bypassing resistance to VEGF- based anti angiogenetic treatments.