AI-03TARGETING ANGIOGENESIS WITHOUT INCREASING THE STROMAL CELL RESPONSE OR INVASION USING ABT-898, A THROMBOSPONDIN TYPE 1 REPEAT PEPTIDE

Anti-angiogenic therapy is a promising therapeutic approach for highly vascularized tumors including glioblastoma (GBM). Nonetheless, the efficacy of Bevacizumab - a monoclonal antibody to VEGF-A - is limited only to progression-free survival but not overall survival, due at least in part to the induction of a more invasive phenotype. Here, we investigated the anti-tumor effect of a thrombospondin-1&2 mimetic peptide, ABT-898, on intracerebral xenografts derived from primary patient GBM neurospheres in the nude mouse. ABT-898 treatment of xenograft tumors (80 mg/kg/day i.p.) prolonged mouse survival. Unlike Bevacizumab-treated mouse brain tumors, ABT-898-treated tumors did not exhibit a detectable increase in the number of invasive foci or phospho-Met expression, indicating no induction of an invasive phenotype. As stromal cells are thought to promote tumor cell invasion, we quantitated infiltration of Iba1+ activated microglial/macrophages into the tumor. Although Bevacizumab therapy significantly increased the number of recruited Iba1+ cells into the tumors, the number of Iba1+ cells in the ABT-898-treated tumors was not increased as compared to the vehicle-treated xenograft tumors. Supporting this finding, the migration of microglia cells (BV2), was significantly inhibited by ABT898 in a dose-dependent manner, and the inhibition was reversed by CD36-neutralizing antibody. This suggests that recruitment of tumor invasion-promoting microglia/macrophage can be regulated by ABT898 and this regulation is in part CD36-dependent. In addition, treatment with ABT898 significantly reduced vessel density in xenograft tumors. In vitro ABT898 induced apoptosis of brain endothelial cells (ECs) and inhibited tubulomorphogenesis in collagen gels, both in a dose-dependent manner, and both were reversed by treatment with CD36 neutralizing antibody, Collectively, these data suggest that ABT-898 offers the novel advantage over Bevacizumab of decreasing stromal cell recruitment to the tumor and thus should be considered as an alternative anti-angiogenic therapy for GBM.