恩扎鲁胺
前列腺癌
雄激素受体
癌症研究
睾酮(贴片)
医学
癌症
内科学
雄激素
抗雄激素
体内
醋酸阿比特龙酯
药理学
内分泌学
肿瘤科
化学
雄激素剥夺疗法
生物
激素
生物技术
作者
Shu Ning,Cameron M. Armstrong,Enming Xing,Amy R. Leslie,Richard Y. Gao,Masuda Sharifi,Zachary A. Schaaf,Wei Lou,Xiangrui Han,Dong Xu,Rui Yang,J. Cheng,Shabber Mohammed,Nicholas Mitsiades,Chengfei Liu,Alan P. Lombard,Chun‐Yi Wu,Xiaolin Cheng,Pui‐Kai Li,Allen C. Gao
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-08-01
标识
DOI:10.1158/0008-5472.can-24-0440
摘要
Abstract The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.
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