Establishment and Characterization of Patient-Derived Xenograft Organoids for Personalized Treatment of Castration-Resistant Prostate Cancer.

Abstract

BACKGROUND: Basic research on castration-resistant prostate cancer (CRPC) is limited by the lack of clinically relevant models. This study aimed to establish patient-derived xenografts (PDX) and PDX-derived organoids from clinical CRPC specimens to develop a bidirectional experimental platform for in vivo xenografts and ex vivo organoids. METHODS: We established a new PDX library (KUCaP PDX series) using CRPC clinical specimens and derived prostate cancer organoids. Comprehensive biological characterization of clinical specimens, PDXs, PDX-derived organoids, and organoid-derived xenografts (ODXs) was performed to confirm the preservation of the original tumor features. Using our PDX library, we conducted genetic engineering and drug testing to explore novel therapeutic approaches. RESULTS: PDX-derived organoids were successfully established from all eight KUCaP PDX lines (100%). Four of the eight lines (50%) were maintained during the long-term culture experiments for over ten passages. Key features observed in the original clinical specimens, including genetic alterations and castration responsiveness, were maintained across the PDX, PDX-derived organoid, and ODX models. RNA sequencing revealed that transcriptomic profiles were consistently maintained across clinical specimens, PDXs, PDX-derived organoids, and ODXs. One PDX and organoid (KUCaP19) which exhibited a high homologous recombination deficiency (HRD) score, without any pathogenic homologous recombination repair (HRR) gene alterations, showed sensitivity to a poly ADP-ribose polymerase (PARP) inhibitor. In contrast, KUCaP12, which had no HRR alterations and a low HRD score, did not respond to PARP inhibition. CONCLUSIONS: We developed the KUCaP library as a novel experimental platform for CRPC research by integrating clinical specimens with PDX, organoid, and ODX models along with their genomic and transcriptomic data. These models largely retained the genetic profiles and responses to castration observed in the original tumors. The bidirectional use of personalized PDX and organoids will facilitate the elucidation of the molecular mechanisms of CRPC.