β1 Integrin Targeting Potentiates Antiangiogenic Therapy and Inhibits the Growth of Bevacizumab-Resistant Glioblastoma

摘要: Antiangiogenic therapies like bevacizumab offer promise for cancer treatment, but acquired resistance, which often includes an aggressive mesenchymal phenotype, can limit the use of these agents. Upregulation β1 integrin (ITGB1) occurs in some bevacizumab-resistant glioblastomas (BRG) whereby, mediating tumor–microenvironment interactions, we hypothesized that it may mediate a mesenchymal-type resistance to antiangiogenic therapy. Immunostaining analyses and its downstream effector kinase FAK revealed upregulation 75% 86% BRGs, respectively, compared with pretreatment paired specimens. Furthermore, flow cytometry eight-fold more primary BRG cells from bevacizumab-naive (BNG). Fluorescence recovery after photobleaching engineered express β1-GFP fusion protein indicated mobile fraction was doubled, half-life turnover focal adhesions reduced markedly bevacizumab-responsive glioblastoma multiforme cells. Hypoxia, increased acquisition associated expression cultured BNG BRGs displayed mesenchymal-like phenotype vitro . We found growth xenograft tumors attenuated by antibody, OS2966, allowing 20-fold dose reduction per cycle this model. Intracranial delivery OS2966 through osmotic pumps over 28 days tumor cell apoptosis, decreased invasiveness, blunted morphology concluded likely reflects onset hypoxia caused therapy, inhibition is well tolerated vivo as tractable strategy disrupt Cancer Res; 73(10); 3145–54. ©2013 AACR