Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.
Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.
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DOI：
10.1111/iju.13137
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Sadar MD
中科院分区：
文献类型：
--
作者：
Imamura Y;Sadar MD
雄激素受体是一种转录因子，是前列腺癌有效的治疗靶点。雄激素剥夺疗法仍然是黄金标准的治疗方法，但它不能治愈，最终这种疾病会以致命的去势抵抗前列腺癌的形式复发。在过去的5年里，随着新的药物被批准，如阿比特龙、苯扎鲁胺、siPuleucel-T、卡巴紫杉醇和Ra-223，治疗环境得到了改善。对晚期疾病耐药机制的新见解正在并已被阐明。目前所有的雄激素受体靶向治疗都是通过阻断雄激素结合激活受体的配体结合域来抑制前列腺癌的生长。有说服力的证据支持这样的概念，即缺乏配体结合结构域的结构性活性雄激素受体剪接变异体是晚期疾病的抗性机制之一。雄激素受体的转录活性需要在其N-末端结构域中有一个功能性的AF-1区域。临床前证据证明，这一领域是预测晚期前列腺癌治疗中潜在范式转变的一个可用药靶点。本文综述了雄激素受体相关的耐药机制，以及与雄激素受体剪接变异体在去势耐受前列腺癌中的表达有关的克服耐药的新的治疗药物。
The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration‐resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel‐T, cabazitaxel and Ra‐223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor‐targeting therapies inhibit the growth of prostate cancer by blocking the ligand‐binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand‐binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF‐1 region in its N‐terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor‐related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration‐resistant prostate cancer.
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