Table_1_Integrating transcriptomics and network analysis-based multiplexed drug repurposing to screen drug candidates for M2 macrophage-associated castration-resistant prostate cancer bone metastases.xlsx

Metastatic castration-resistant prostate cancer (CRPC) has long been considered to be associated with patient mortality. Among metastatic organs, bone is the most common metastatic site, with more than 90% of advanced patients developing bone metastases (BMs) before 24 months of death. Although patients were recommended to use bone-targeted drugs represented by bisphosphonates to treat BMs of CRPC, there was no significant improvement in patient survival. In addition, the use of immunotherapy and androgen deprivation therapy is limited due to the immunosuppressed state and resistance to antiandrogen agents in patients with bone metastases. Therefore, it is still essential to develop a safe and effective therapeutic schedule for CRPC patients with BMs. To this end, we propose a multiplex drug repurposing scheme targeting differences in patient immune cell composition. The identified drug candidates were ranked from the perspective of M2 macrophages by integrating transcriptome and network-based analysis. Meanwhile, computational chemistry and clinical trials were used to generate a comprehensive drug candidate list for the BMs of CRPC by drug redundancy structure filtering. In addition to docetaxel, which has been approved for clinical trials, the list includes norethindrone, testosterone, menthol and foretinib. This study provides a new scheme for BMs of CRPC from the perspective of M2 macrophages. It is undeniable that this multiplex drug repurposing scheme specifically for immune cell-related bone metastases can be used for drug screening of any immune-related disease, helping clinicians find promising therapeutic schedules more quickly, and providing reference information for drug R&D and clinical trials.

转移性去势抵抗性前列腺癌（Metastatic castration-resistant prostate cancer, CRPC）长期以来被认为与患者死亡风险密切相关。在各类转移器官中，骨骼是最常见的转移部位，超过90%的晚期患者会在死亡前24个月内出现骨转移（bone metastases, BMs）。尽管临床推荐采用以双膦酸盐类药物为代表的骨靶向疗法治疗CRPC骨转移，但患者的整体生存并未得到显著改善。此外，由于骨转移患者存在免疫抑制状态及抗雄激素药物耐药性，免疫治疗与雄激素剥夺疗法的应用均受到极大限制。因此，开发针对合并骨转移的CRPC患者的安全有效治疗方案仍具有重要的临床价值。为此，本研究提出了一种基于患者免疫细胞组成差异的多药物重定位方案。通过整合转录组学与基于网络的分析方法，从M2型巨噬细胞的视角对候选药物进行优先级排序。同时，结合计算化学与临床试验数据，通过药物冗余结构筛选，生成了针对CRPC骨转移的综合候选药物清单。该清单除已获批用于临床应用的多西他赛外，还包含炔诺酮、睾酮、薄荷醇与福替尼。本研究从M2型巨噬细胞的角度为CRPC骨转移的治疗提供了全新的策略。不可否认，这种针对免疫细胞相关骨转移的多药物重定位方案可推广至任意免疫相关疾病的药物筛选工作，能够帮助临床医师更快速地发掘具有潜力的治疗方案，并为药物研发与临床试验提供重要的参考依据。