Related Experiment Video
Updated: Jul 5, 2025
Translational Orthotopic Models of Glioblastoma Multiforme
Published on: February 17, 2023
Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants
Nomi Zalcman1,2, Liraz Larush3, Haim Ovadia2
1Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Abstract:
The median survival time of patients with an aggressive brain tumor, glioblastoma, is still poor due to ineffective treatment. The discovery of androgen receptor (AR) expression in 56% of cases offers a potential breakthrough. AR antagonists, including bicalutamide and enzalutamide, induce dose-dependent cell death in glioblastoma and glioblastoma-initiating cell lines (GIC). Oral enzalutamide at 20 mg/kg reduces subcutaneous human glioblastoma xenografts by 72% (p = 0.0027). We aimed to further investigate the efficacy of AR antagonists in intracranial models of human glioblastoma. In U87MG intracranial models, nude mice administered Xtandi (enzalutamide) at 20 mg/kg and 50 mg/kg demonstrated a significant improvement in survival compared to the control group (p = 0.24 and p < 0.001, respectively), confirming a dose-response relationship. Additionally, we developed a newly reformulated version of bicalutamide, named "soluble bicalutamide (Bic-sol)", with a remarkable 1000-fold increase in solubility. This reformulation significantly enhanced bicalutamide levels within brain tissue, reaching 176% of the control formulation's area under the curve. In the U87MG intracranial model, both 2 mg/kg and 4 mg/kg of Bic-sol exhibited significant efficacy compared to the vehicle-treated group (p = 0.0177 and p = 0.00364, respectively). Furthermore, combination therapy with 8 mg/kg Bic-sol and Temozolomide (TMZ) demonstrated superior efficacy compared to either Bic-sol or TMZ as monotherapies (p = 0.00706 and p = 0.0184, respectively). In the ZH-161 GIC mouse model, the group treated with 8 mg/kg Bic-sol as monotherapy had a significantly longer lifespan than the groups treated with TMZ or the vehicle (p < 0.001). Our study demonstrated the efficacy of androgen receptor antagonists in extending the lifespan of mice with intracranial human glioblastoma, suggesting a promising approach to enhance patient outcomes in the fight against this challenging disease.
Insights
Androgen receptor (AR) antagonists show promise for treating glioblastoma. Enzalutamide and a new soluble bicalutamide formulation significantly extended survival in preclinical models, suggesting a new therapeutic avenue for this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Glioblastoma (GBM) remains a challenging brain tumor with poor median survival due to limited treatment efficacy.
- Androgen receptor (AR) expression in 56% of GBM cases presents a potential therapeutic target.
- AR antagonists have demonstrated dose-dependent cell death in GBM and glioblastoma-initiating cell lines (GIC).
Purpose of the Study:
- To investigate the efficacy of AR antagonists in intracranial models of human glioblastoma.
- To evaluate a newly reformulated, highly soluble bicalutamide (Bic-sol) for enhanced brain penetration and efficacy.
- To assess the combination therapy of Bic-sol with Temozolomide (TMZ) for glioblastoma treatment.
Main Methods:
- Administered oral enzalutamide (20 and 50 mg/kg) to nude mice with U87MG intracranial glioblastoma xenografts.
- Developed and administered a novel soluble bicalutamide (Bic-sol) formulation (2 and 4 mg/kg) to U87MG intracranial models.
- Evaluated combination therapy of Bic-sol (8 mg/kg) with TMZ in U87MG and ZH-161 GIC mouse models.
Main Results:
- Enzalutamide significantly improved survival in intracranial U87MG models, showing a dose-response relationship.
- Soluble bicalutamide (Bic-sol) demonstrated significant efficacy in U87MG intracranial models, with enhanced brain tissue levels.
- Combination therapy with Bic-sol and TMZ showed superior efficacy over monotherapies in both U87MG and ZH-161 models, significantly extending lifespan.
Conclusions:
- Androgen receptor antagonists, including enzalutamide and soluble bicalutamide, are effective in extending survival in preclinical intracranial glioblastoma models.
- The enhanced solubility and brain penetration of Bic-sol contribute to its therapeutic efficacy.
- Combination therapy with AR antagonists and standard chemotherapy (TMZ) offers a promising strategy to improve outcomes for glioblastoma patients.
