MTR-15A PRONEURAL SIGNATURE PROFILE PREDICTS RESISTANCE TO BEVACIZUMAB THERAPY IN GLIOBLASTOMA

Abstract

Glioblastoma, the most common adult glioma, has a dismal prognosis. Treatment with bevacizumab has not significantly prolonged overall survival. Glioblastoma resistance to angiogenesis inhibitors is attributed to interacting mechanisms. We thus began a comprehensive effort to detect expression signatures associated with therapeutic response, which might facilitate prospective selection of patients who are likely to respond to therapy. The Notch signaling pathway is an evolutionarily conserved pathway that is important in multiple cellular and developmental processes, including cell fate decision, differentiation, proliferation, survival, angiogenesis, and migration. Analysis of The Cancer Genome Atlas expression dataset identified a group of tumors with a proneural signature showing high Notch pathway activation. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. Tumor samples were collected from 27 patients at the time of tumor recurrence, and immunohistochemical techniques were used to compare expression of CD133, Notch-1, and VEGF. Expressions of CD133-, Notch-1–, and VEGF-positive glioma cells were higher in recurrent glioblastomas after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy before undergoing a second surgery at recurrence. Overall survival was significantly longer in Notch-1–negative patients (8.8 months) than in Notch-1–positive patients (6.8 months). Our results show that proneural glioblastoma with high Notch pathway activation is associated with resistance to bevacizumab therapy.