前列腺癌是我国男性中发病率增长最快的癌症。临床上采用类固醇代谢酶抑制剂阿比特龙治疗晚期前列腺癌。约30%的患者天然耐受阿比特龙，且鉴别药物适用人群的生物标志物缺失。我们前期研究发现：患者服用阿比特龙后血液中黄体酮丰度显著上升；黄体酮能够被前列腺癌细胞代谢为不同的产物并调节雄激素受体转录活性。因此，黄体酮及其代谢物可能介导了患者对阿比特龙的个体化响应。本项目拟利用细胞、小鼠等模型，解析黄体酮在前列腺癌中的代谢途径；阐释黄体酮及其代谢物调控前列腺癌细胞激素代谢、信号转导等生命活动的机制；探索长期高浓度黄体酮处理对前列腺癌细胞的影响；结合临床数据，在不同雄激素受体基因型患者中建立黄体酮丰度与药物响应之间的关联。本项目成果将从类固醇激素代谢的角度揭示药物耐受及药物响应个体化差异的分子机制，明确阿比特龙适用人群的生理特征（血液中黄体酮浓度）和基因特征（雄激素受体基因型），推动个体化治疗的开展。

Prostate cancer is the fastest increasing cancer in China in man. Abiraterone, targeting to steroidogenic enzyme, is used for castration resistant prostate cancer (CRPC) treatment. However, ~30% of the patients are primary resistance to abiraterone and the biomarkers to identify abiraterone responders are missing. We have found that patients receiving abiraterone have varied increase of circulating progesterone, which might correlate with its clinical response. Progesterone could be metabolized in prostate cancer cells and regulate androgen receptor (AR) transcriptional activity. This proposal is dedicated to clarify the metabolic pathway of progesterone in prostate cancer, to investigate the effects of progesterone on androgen metabolism and AR signaling, to demonstrate the long term effects of progesterone in prostate cancer, to establish the correlation between progesterone alteration and abiraterone response in patients with different AR genotypes. The results from this project will provide biomarkers including the physiological progesterone concentration and AR genotypes to predict abiraterone response in clinic.