Oncotarget | The oral tubulin-binder BAL101553 is associated with inhibition


Oncotarget Volume 11, Issue 8 reported that 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 according to EB1 expression-level and to decipher its mechanism of action on GBM stem cells.

Altogether, the Research Team's 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.

Dr. Diane Braguer from Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France as well as APHM, CHU Timone, Marseille 13385, Franceand & Dr. Heidi A. Lane from Basilea Pharmaceutica International Ltd., Basel, Switzerland said, "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."

The high heterogeneity due to functionally diverse cell types, hypervascularization and the infiltrative nature of GBM tumor cells contributes to resistance to chemo and radiotherapy.

Cancer stem cells represent a subpopulation of cells within GBM that are characterized by increased resistance to chemotherapy and radiotherapy, suggesting that stem cells are likely responsible for the failure of treatment and high recurrence rates.

"Stem cells are likely responsible for the failure of treatment and high recurrence rates"

- Dr. Diane Braguer, Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol

Therefore, GBM stem cells are considered as a relevant target for GBM therapy, and the elimination of these cells is crucial in treating GBM. GBM stem cells have been reported to directly contribute to the tumor vasculature through trans-differentiation into endothelial cells.

Furthermore, the connection between neural stem cells and the endothelial compartment seems to be critical in GBM, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor-a and stromal-derived factor 1.

Figure 1: BAL101553 treatment enhances survival and reduces tumor growth in mice orthotopically grafted with GBM6 cells.

Figure 1: BAL101553 treatment enhances survival and reduces tumor growth in mice orthotopically grafted with GBM6 cells. Mean weights of control GBM6-GFP-sh0 (A) or EB1-down-regulated GBM6-GFP-shEB1 bearing mice (B) orally treated with BAL101553 or vehicle for 100 days (pale orange square). Kaplan–Meier survival plot of GBM6-GFP-sh0 (C) or GBM6-GFP-shEB1 bearing mice (D). Three-dimensional reconstruction of brains with tumors (green) (millimiter-scale). A, anterior; D, dorsal; L, lateral; M, medial; P, posterior; V, ventral (E)

The Braguer/Lane Research Team concluded in their Oncotarget Research Paper, "these results show that BAL101553 counteracts the formation of brain tumor vessels by inhibiting GBM stem cell trans-differentiation in tumor-derived endothelial cells, as well as VEGF secretion; thus, cutting off the tumor from blood and nutrition supply and potentially adding to the direct anti-tumor cell effect. A high level of EB1 expression in CSLCs potentiates the drug effects, further supporting the potential of EB1 expression as a BAL101553 response-predictive biomarker in GBM."

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DOI - https://doi.org/10.18632/oncotarget.27374

Full text - https://www.oncotarget.com/article/27374/text/

Correspondence to - Diane Braguer - [email protected] and Heidi A. Lane - [email protected]

Keywords - glioblastoma, cancer stem cells, microtubule-targeting agent, experimental cancer therapeutics

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