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計畫

負責人

計畫重點

計畫主持人

徐宗溢

To elucidate molecular mechanism of neurosteroids synthesis in glioblastoma.

子計畫二

莊健盈

To investigate effect of HDAC inihibtion on AR-induced drug resistance in glioblastoma.

子計畫三

陳瑞明

To investigate the role of AR-induced AQP4 expression  in drug resistance of glioblastoma.

子計畫四

劉景平

To discover, through chemical modification, potential compounds targeting HDAC and CYP17A1 for glioblastoma.

 

 

研究主題:To clarify the therapeutic effect of strategies for targeting the neurosteroid-androgen receptor axis on TMZ-resistant glioblastoma

研究摘要

  Androgen receptor (AR) overexpression was shown to promote drug resistance in prostate cancer. However, the role of AR in acquiring resistance of glioblastoma enriched by androgen-typed neurosteroids remains unclear. Herein, we observed ALZ003, a curcumin analog, induced FBXL2-mediated AR ubiquitination, leading to degradation. Compared with FDA-approved AR inhibitor, enzalutamide, ALZ003 exhibited higher activity in degrading AR and in suppressing tumor growth. Importantly, ALZ003 significantly inhibited the survival of glioblastoma with or without temozolomide (TMZ) resistance. The dysregulation of redox homeostasis, and characteristics of ferroptosis, including glutathione peroxidase (GPX) 4 downregulation, were significantly induced by ALZ003, not by enzalutamide. Furthermore, we found that AR regulated GPX4 expression, and overexpression of AR prevented ferroptosis in the presence of GPX4. In addition to inhibiting the growth of glioblastoma in the orthotopic mouse model, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Particularly, ALZ003 synergistically suppressed growth of glioblastoma with TMZ in the orthotopic model. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-induced AR degradation provide a new insight into therapeutic strategy for TMZ resistant glioblastoma.

研究成果