肿瘤代谢重塑相关新促癌因子的鉴定、功能和干预策略

前列腺癌是雄激素驱动的男性高发癌症。临床治疗通过抑制雄激素合成来治疗前列腺癌，然而治疗耐受不可避免，暗示了肿瘤代谢重塑的发生和新促癌代谢物的存在。项目前期数据显示，接受阿比特龙治疗的前列腺癌患者体内胆固醇-甾体代谢从雄激素合成转向孕酮合成方向；治疗耐受的患者孕酮血液含量显著升高。本项目将深入研究该代谢重塑影响疾病进展的分子机制、干预策略和临床意义。本项目将利用孕酮瞬时或长期处理前列腺癌细胞系，结合二代测序等技术，解析孕酮促进前列腺癌进展的分子机制，并在类器官、小鼠模型中进一步验证；探索孕酮合成路径及相关代谢物在前列腺癌疾病进展中的生理功能，通过干预孕酮的合成，为前列腺癌治疗提供新的策略；分析患者体内孕酮丰度与治疗响应的相关性，明确该代谢重塑的临床意义。项目成果将揭示临床治疗应激条件下，机体代谢重塑影响疾病进展的新机制和相关干预策略，为前列腺癌临床诊治提供新的生物标志物和治疗策略。

Androgen sustains prostate cancer development. Disease progression is temporarily postponed by medicine suppressing the steroidogenic pathway, indicating the existence of novel onco-metabolites beyond androgens. Previously, we have found a significant increase of progesterone in patients receiving abiraterone treatment, indicating a switch of cholesterol-steroid metabolism from androgens to progesterone. Here we propose to investigate the clinical significance of progesterone, the related mechanisms of progesterone to stimulate disease progression, and the potential intervention strategy. The potential correlation between plasma concentration of progesterone and treatment response would be evaluated. The transient effect and long term effect of progesterone on prostate cancer cell lines will be investigated and the related mechanisms will be validated in organoids and mouse model. The synthesis pathway of progesterone will be investigated to develop novel strategy for prostate cancer therapy by inhibiting the generation of progesterone. Our results will unveil the significance and novel mechanism of metabolic remodeling in the development of prostate cancer, providing potential biomarker and treatment for disease management.