EP4受体拮抗剂ZH439联合PD1抗体抑制去势抵抗性前列腺癌（CRPC）的功能和机制研究

我国前列腺癌发病率持续上升，且大多数最终进展为去势抵抗性前列腺癌（CRPC），严重危害健康。但目前CRPC的临床药物和免疫疗法总体疗效欠佳，CRPC新药研发一直是难点。小分子化合物是新药重要源泉，发现肿瘤免疫微环境新靶点、鉴定新型抗CRPC的小分子并阐明其功能和机理具有重要意义。申请者前期发现EP4受体是前列腺癌免疫治疗的特异靶点，并鉴定一种新型靶向EP4受体的小分子ZH439，ZH439联合PD1抗体显著减少前列腺癌微环境MDSC浸润并抑制其功能、促进T细胞招募并增强其功能，且抑制CRPC生长。但尚不清楚其抗CRPC转移的功能和具体机制。本项目围绕核心假设——ZH439通过靶向EP4受体、联合PD1抗体抑制CRPC生长和转移，采用单细胞测序、多色流式和人源化模型等方法，探究ZH439抗CRPC新的功能和机理。本研究对阐明小分子化合物与PD1抗体联用抗肿瘤分子机制及新药研发具有重要意义。

The incidence of prostate cancer shows an upward trend in China. Most prostate cancers eventually develop into castration resistant prostate cancer (CRPC) and seriously harm health. However, the current clinical drugs and immunotherapy for CRPC are showed insufficient effectiveness, and it is constantly being challenged to research and develop novel CRPC drugs. Small molecule compounds are important sources of new drug. It is of great significance to discover new targets of tumor immune microenvironment， identify new small molecule of anti-CRPC and elucidate its function and mechanism. The applicant previously found that EP4 receptor was a specific target for immunotherapy of prostate tumor, and identified a new small molecule ZH439 targeting EP4 receptor. ZH439 not only combined with PD1 antibody but also significantly reduced MDSC infiltration in tumor microenvironment and inhibited its function. Furthermore, ZH439 also promotes T cell recruitment and enhances its function, and then inhibited the growth of prostate cancer. However, the function and detailed mechanism of anti-CRPC of ZH439 are still unknown. This project focuses on the core hypothesis——ZH439 combines with PD1 antibody and inhibits CRPC growth and metastasis by targeting EP4 receptor, to study the novel function and mechanism of ZH439 inhibiting CRPC through combining with PD1 antibody using some assays including single-cell sequencing, multicolor flow and humanized mouse model. This study is of great significance to clarify the anti-tumor molecular mechanism of small molecule compounds combined with PD1 antibody and develop new drugs.