EB1-dependent long survival of glioblastoma-grafted mice with the oral tubulin-binder BAL101553 is associated with inhibition of tumor angiogenesis.

Raphaël Bergès,Heidi A Lane,Felix Bachmann,Dominique Figarella-Branger,Aurélie Tchoghandjian,Diane Braguer,Arnauld Sergé,Stéphane Honoré

doi:10.18632/oncotarget.27374

Abstract

Glioblastoma (GBM) are aggressive brain tumors with limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness, representing promising targets. BAL101553, a prodrug of BAL27862, is a novel small molecule tubulin-binding agent, promoting tumor cell death through spindle assembly checkpoint activation, which is currently in Phase 1/2a in advanced solid tumor patients including GBM. This study aimed to evaluate long-term daily oral BAL101553 treatment of mice orthotopically grafted with GBM CSLCs (GBM6) according to EB1 expression-level, and to decipher its mechanism of action on GBM stem cells. Oral treatment with BAL101553 for 100 days provoked a large EB1 expression level-dependent survival benefit, together with a decrease in tumor growth and brain invasion. Formation of vascular structures by the fluorescent GBM6-GFP-sh0 cells, mimicking endothelial vascular networks, was observed in the brains of control grafted mice. Following BAL101553 treatment, vessels were no longer detectable, suggesting inhibition of the endothelial trans-differentiation of GBM stem cells. In vitro, BAL27862 treatment resulted in a switch to the endothelial-like phenotype of GBM6 towards an astrocytic phenotype. Moreover, the drug inhibited secretion of VEGF, thus preventing normal endothelial cell migration activated by CSLCs. The decrease in VEGF secretion was confirmed in a human GBM explant following drug treatment. Altogether, our data first confirm the potential of EB1 expression as a response-predictive biomarker of BAL101553 in GBM we previously published and add new insights in BAL101553 long-term action by counteracting CSLCs mediated tumor angiogenesis. Our results strongly support BAL101553 clinical studies in GBM patients.

Highlights

Glioblastoma (GBM) are the most frequent and aggressive primary brain tumors in adults with a median survival of only 15 months with the current standard of care [1]
Our study shows for the first time that BAL101553 treatment counteracts tumor angiogenesis by acting on Cancer stem-like cells (CSLCs) in an End-binding 1- protein (EB1)-dependent manner and provides new insights into the therapeutic targeting of CSLCs
Long-term daily oral BAL101553 treatment enhances survival, reduces tumor growth and invasion in mice orthotopically grafted with GBM6; an effect potentiated by EB1 expression

Summary

Introduction

Glioblastoma (GBM) are the most frequent and aggressive primary brain tumors in adults with a median survival of only 15 months with the current standard of care [1]. The high heterogeneity due to functionally diverse cell types, hypervascularisation and the infiltrative nature of GBM tumor cells contributes to resistance to chemo-and radiotherapy [2, 3]. Cancer stem cells represent a subpopulation of cells within GBM that are www.oncotarget.com characterized by increased resistance to chemotherapy and radiotherapy, suggesting that stem cells are likely responsible for failure of treatment and high recurrence rates [4,5]. Cancer stem cells are capable of infinite selfrenewal and multi-potential differentiation [6]. GBM stem cells can initiate very aggressive tumor formation when implanted in xenograft models. GBM stem cells are considered as a relevant target for GBM therapy, and the elimination of these cells is crucial in treating GBM

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