Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Int J Mol Sci. 2023 Dec 26;25(1):332. doi: 10.3390/ijms25010332.
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% ( = 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 ( = 0.24 and < 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 ( = 0.0177 and = 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 ( = 0.00706 and = 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 ( < 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.
由于治疗效果不佳，侵袭性脑肿瘤胶质母细胞瘤患者的中位生存时间仍然较差。在 56%的病例中发现雄激素受体 (AR) 表达，这为治疗提供了一个潜在的突破。AR 拮抗剂，包括比卡鲁胺和恩扎鲁胺，在胶质母细胞瘤和胶质母细胞瘤起始细胞系 (GIC) 中诱导剂量依赖性细胞死亡。口服恩扎卢胺 20mg/kg 使皮下人胶质母细胞瘤异种移植减少 72%（=0.0027）。我们旨在进一步研究 AR 拮抗剂在颅内胶质母细胞瘤模型中的疗效。在 U87MG 颅内模型中，与对照组相比，接受 Xtandi（恩扎鲁胺）20mg/kg 和 50mg/kg 治疗的裸鼠的生存时间显著改善（=0.24 和 <0.001），证实了剂量反应关系。此外，我们开发了一种新的比卡鲁胺配方，名为“可溶性比卡鲁胺（Bic-sol）”，其溶解度提高了 1000 倍。这种配方显著增加了脑组织内的比卡鲁胺水平，达到对照配方曲线下面积的 176%。在 U87MG 颅内模型中，与载体处理组相比，2mg/kg 和 4mg/kg 的 Bic-sol 均显示出显著疗效（=0.0177 和 =0.00364）。此外，与比卡鲁胺或 TMZ 单药治疗相比，8mg/kg Bic-sol 和 Temozolomide（TMZ）联合治疗显示出更好的疗效（=0.00706 和 =0.0184）。在 ZH-161 GIC 小鼠模型中，与 TMZ 或载体处理组相比，接受 8mg/kg Bic-sol 单药治疗的小鼠的寿命显著延长（<0.001）。我们的研究表明，雄激素受体拮抗剂在延长颅内人胶质母细胞瘤小鼠的寿命方面具有疗效，这为改善患者在治疗这种具有挑战性的疾病方面的预后提供了一种有前途的方法。
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