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.

Microtubules (MT) a key target in oncology: mathematical modeling of anti-MT agents on cell migration

“…The next step will be to identify the dose response eects of drugs on the parameters of the model. Another development track concerns also the action of other MTAs such as paclitaxel, a stabilizing agent or new MTAs such as BAL 101553 [6].…”

A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors

“…We built three subcutaneous xenograft models by transplanted HeLa, HeLaR or K562 cells into nude mice. When the tumor volume reached approximately 100 mm 3 , the nude mice were randomly assigned to three groups that were intraperitoneal administered 25 mg/kg MP-HJ-1b, 0.2 mg/kg vincristine, or corn oil, respectively. For tumors derived from HeLa and K562 cells, both compounds inhibited tumor growth and showed excellent anticancer activity (Fig.…”

“…Microtubule is considered as one of the most important targets of anticancer drugs due to its important role in cell mitosis (1)(2)(3). Microtubule inhibitors, which inhibit cell growth by binding on microtubules and further influencing microtubules' function, have been used with great success in the treatment of variety of tumors (4,5).…”

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

“…It is a very potent inhibitor of tumor cell growth and promoter of cell death, whose activity is associated with activation of the spindle assembly checkpoint. Moreover, the drug is efficiently distributed into the brain and the tumor, with anticancer activity in GBM models, thus providing a strong rationale for its use for GBM treatment [16]. We recently demonstrated the anticancer activity of BAL27862 (in vitro) and its prodrug BAL101553 (xenografts) on the GBM cancer stem-like cell (CSLC) model GBM6.…”