BAL101553 activity on glioblastoma stem-like cells

Glioblastoma (GBM) patients have limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM 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 1/2 clinical development. Broad anti-cancer 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 GBM progression and poor survival. Here, we show that BAL27862 inhibits the growth of two GBM CSLCs. As EB1 is overexpressed in the CSLCs line GBM6, that display 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 sub-cytotoxic concentrations in EB1-expressing control cells (GBM6-sh0) but only at cytotoxic concentrations in EB1-down-regulated (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 anti-proliferative and anti-invasive effects of BAL101553 were more potent in mice bearing control tumors than EB1-down-regulated 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 GBM treatment, with EB1 expression as a predictive biomarker of response.

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