SPP1介导的新型抗雄激素药物治疗去势抵抗性前列腺癌的耐药形成机制及靶向干预研究

Castration-resistant prostate cancer (CRPC) is commonly associated with bone metastasis, and cross-resistance of new anti-androgen drugs often occurs during the CRPC treatment. However, the mechanism of drug resistance is far from being elucidated. Based on the single-cell sequencing of enzalutamide resistant and bone metastasis CRPC tumor-bearing mice and the gene chip combination analysis of GEO database, we found that the extracellular matrix SPP1 is closely related to the development of CRPC resistance, and significantly high expression of SPP1 was observed in abiraterone resistant CRPC organoid model. This project intends to further validate the relationship between SPP1 and the development of CRPC using clinical specimens. Then, based on the human bone metastasis prostate organoids and tumor-bearing mouse model, we will investigate the regulation of SPP1 binding to its receptors on downstream signaling pathway and androgen receptor expression. In order to find drugs that can block the interaction between SPP1 and its receptors, we will apply molecular docking, molecular dynamics simulation and protein chip technology into drug repositioning study, and verify the candidates’ efficacy against bone metastasis CRPC resistance through in vitro and in vivo experiments. This study aims to reveal the mechanism of drug resistance in bone metastasis CRPC and provides novel biomarker and target for its diagnosis and treatment.

去势抵抗性前列腺癌（CRPC）常伴有骨转移，并且在新型抗雄激素药物治疗过程中会产生交叉耐药现象，然而其耐药机制还远未阐明。我们前期基于骨转移CRPC恩杂鲁胺耐药的荷瘤鼠模型的单细胞测序结果及GEO数据库的基因芯片联合分析，发现细胞外基质SPP1与CRPC耐药性发展密切相关，并且在阿比特龙耐药的CRPC类器官中也呈显著性高表达。本项目拟利用临床样本进一步验证SPP1与CRPC发生和发展的相关性，并基于人源骨转移前列腺癌类器官及骨转移CRPC荷瘤鼠模型，探究SPP1与其受体结合后对下游信号通路及雄激素受体表达的调控作用。在此基础上，为了发现能够阻断SPP1与其受体相互作用的药物，本项目利用分子对接、分子动力学模拟及蛋白质芯片技术，进行上市药物的重定位研究，并通过体内外实验验证其抵抗CRPC耐药产生的可行性。本研究旨在揭示骨转移CRPC的耐药形成机制，并为其诊疗提供新的生物标志物和干预靶点。

前列腺癌是全球范围内男性第二大恶性肿瘤，随着人口老龄化的加剧，前列腺癌成为我国男性泌尿系统肿瘤之首，是近十年来增速最快的男性恶性肿瘤之一。内分泌治疗是晚期前列腺癌的首选治疗方式，在治疗12至24个月后不可避免地会产生去势抵抗，发展为去势抵抗性前列腺癌(CRPC)。耐药问题是CRPC治疗难点与痛点。因此，亟需开发基于临床需求的CRPC新型治疗药物。.本项目研究发现细胞外基质SPP1与整合素αvβ3受体相互作用介导前列腺癌抗雄激素药物治疗耐药。因此，基于虚拟筛选、表面等离子共振技术、分子动力学模拟等技术发现了具有抗前列腺癌活性的高亲和力的新型αvβ3抑制剂。在细胞、类器官及动物水平上证明，新型αvβ3抑制剂的药效优于恩杂鲁胺，并且具有良好的安全性，本项目为CRPC治疗提供新机制、新靶点、新治疗药物。目前相关研究已授权国内专利及PCT专利。. “十四五”时期是应对人口老龄化的重要窗口期，前列腺癌作为中老年男性高发的恶性肿瘤，对其开展基于临床需求的基础研究与创新药物转化应用研究，关乎民生、国家重大科技创新。本成果将为自主知识产权的创新药物研发积累转化基础，具有重要的临床应用价值。