title: The Novel Tubulin-Binding Checkpoint Activator BAL101553 Inhibits EB1-Dependent Migration and Invasion and Promotes Differentiation of Glioblastoma Stem-like Cells.
abstract: Glioblastoma patients have limited treatment options. Cancer stem-like cells (CSLC) contribute to glioblastoma invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the spindle assembly checkpoint, which is currently in phase I/II clinical development. Broad anticancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments. We have shown that overexpression of microtubule + end-binding 1-protein (EB1) correlates with glioblastoma progression and poor survival. Here, we show that BAL27862 inhibits the growth of two glioblastoma CSLCs. As EB1 is overexpressed in the CSLC line GBM6, which displays a high tumorigenicity and infiltrative pattern of migration in vivo, we investigated drug activity on GBM6 according to EB1 expression. BAL27862 inhibited migration and colony formation at subcytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-downregulated (GBM-shE1) cells. Three administrations of BAL101553 were sufficient to provoke an EB1-dependent survival benefit in tumor-bearing mice. Patterns of invasion and quantification of tumor cells in brain demonstrated that GBM6-sh0 cells were more invasive than GBM6-shEB1 cells, and that the antiproliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than in EB1-downregulated tumors. This was associated with inhibition of stem cell properties in the GBM6-sh0 model. Finally, BAL27862 triggered astrocytic differentiation of GBM6 in an EB1-dependent manner. These results support the potential of BAL101553 for glioblastoma treatment, with EB1 expression as a predictive biomarker of response. Mol Cancer Ther; 15(11); 2740-9. ©2016 AACR.
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Bergès
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Tchoghandjian
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France.|APHM, CHU Timone, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Honoré
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France.|APHM, CHU Timone, Marseille, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Estève
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France.|APHM, CHU Timone, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Bachmann
authors.affiliation: Basilea Pharmaceutica International Ltd., Basel, Switzerland. diane.braguer@univ-amu.fr heidi.lane@basilea.com.
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Lane
authors.affiliation: Aix Marseille Univ, INSERM, CRO2 UMR911, Marseille, France. diane.braguer@univ-amu.fr heidi.lane@basilea.com.|APHM, CHU Timone, Marseille, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Braguer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010069:Oxadiazoles / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D010069:Oxadiazoles; D050257:Tubulin Modulators; C000599741:lisavanbulin