Abstract 774: Notch pathway activation predicts resistance to bevacizumab therapy in glioblastoma

Abstract

Glioblastoma, the most common adult glioma, is associated with a dismal prognosis. Treatment with bevacizumab has not significantly prolonged overall patient survival times. Glioblastoma resistance to angiogenesis inhibitors is attributed to multiple interacting mechanisms. We have thus embarked on a comprehensive effort to detecting expression signatures that are associated with response to the therapy and these signatures may allow prospective selection of patients with high likelihood of responding to therapy. Notch signaling pathway is an evolutionarily conserved pathway that plays an important role 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 (43.9%) of tumors with 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. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with Notch-1 positivity (6.8 months). Electron microscopic observation of two autopsy cases revealed the effects of blood vessel normalization in Notch-1 positive glioblastoma. Electron microscopic images confirmed the presence of pericytes surrounding the vascular endothelium. Autopsied tumors exhibited marked proliferation of Notch-1 and VEGF positive cells around vessels. In tumor angiogenesis, vascular endothelial growth factor and Notch signaling induce sprouting angiogenesis and recruitment of vascular endothelial cells such as tip cells, stalk cells, and phalanx cells. Fully mature phalanx cells are in close contact with pericytes. These findings indicate that bevacizumab treatment promotes vascular normalization by recruiting mature pericytes and associated with resistance to bevacizumab therapy in glioblastoma with high Notch pathway activation. Citation Format: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Junya Iwama, Masashi Ikota, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Takatoshi Sakurai, Satoshi Iwabuchi. Notch pathway activation predicts resistance to bevacizumab therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2017-774

SPOPL induces tumorigenicity and stemness in glioma stem cells by activating Notch signaling

“…Nonetheless, NICD is widely acknowledged as an important marker of Notch pathway activation, which indicates that SPOPL could regulate the Notch signaling pathway in GSCs. There is extensive evidence that the Notch signaling pathway plays an important role in the regulation of cellular fate, proliferation, and migration, as well as in the maintenance of the resting state of the cell and in regulating the differentiation of neural stem cells (NSCs) [31]. Emerging evidence suggests that the extracellular matrix protein Tenascin-C can activate the Notch signaling pathway in GSCs [32].…”

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

“…It has been previously confirmed that the Notch signaling pathway is critically associated with stem cell fate determination, proliferation, maintenance of cell quiescence, metastasis, and modulation of differentiation of both normal NSCs and GSCs ( 124 ). Via mutual effects with ligands on a considerable number of cells, the Notch pathway, including the four Notch receptors (Notch 1–Notch 4) and five ligands (Jagged-1 and Jagged-2, and Delta-like-1, Delta-like-3, and Delta-like-4), can regulate the interaction between cells and neighboring cells covering a short range ( 125 , 126 ).…”

Therapeutic strategies of recurrent glioblastoma and its molecular pathways ‘Lock up the beast’

“…Notch pathway is important for determination of cell fate, proliferation, maintenance of cell quiescence, migration and regulate neural stem cell differentiation [134]. It starts by activation of γ-secretase by the jagged family ligands which leads to cleavage of notch receptors, then the intracellular notch receptor domain (NICD) translocates to the nucleus and formation of recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and Mastermind-like 1 (MAML) complexes in the nucleus and activation of the hairy and enhancer of split (HES) and HEY genes that maintain multi-potency [135] (Figure 7).…”