Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-a...Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-assembly nanotechnology,we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect.Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor,utilizing the spatial distance self-adaptive characteristics of its nanostructure.In the 22Rv1 cell model,Nano-PROTAC degraded 80%of the AR protein and 65%of the HSP90 protein.More importantly,nano-PROTAC could degrade 74%of the AR splice variant AR-V7 protein,showing the potential ability to overcome drug resistance.We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC.Compared with the combination treatment group of AR and HSP90 inhibitors(enzalutamide and pimitespib),the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78%and a median survival extension of 15 days.Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA-and AR-positive castration-resistant prostate cancer,except for neuroendocrine prostate cancer,which provides a new therapeutic strategy for the treatment of prostate cancer.展开更多
基金supported by the National Natural Science Foundation of China(52322308,52273126)the National Key R&D Program of China(2022YFA1205700,2022YFE0200800)the Beijing Nova Program(20240484673,20230484237).
文摘Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies,posing a challenge in clinical treatment.In this study,on the basis of in vivo self-assembly nanotechnology,we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect.Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor,utilizing the spatial distance self-adaptive characteristics of its nanostructure.In the 22Rv1 cell model,Nano-PROTAC degraded 80%of the AR protein and 65%of the HSP90 protein.More importantly,nano-PROTAC could degrade 74%of the AR splice variant AR-V7 protein,showing the potential ability to overcome drug resistance.We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC.Compared with the combination treatment group of AR and HSP90 inhibitors(enzalutamide and pimitespib),the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78%and a median survival extension of 15 days.Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA-and AR-positive castration-resistant prostate cancer,except for neuroendocrine prostate cancer,which provides a new therapeutic strategy for the treatment of prostate cancer.
