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Introduction: An important clinical need remains to improve survival of men with advanced metastatic prostate cancer (PCa). A better understanding of the mechanisms underlying PCa progression and treatment resistance is a prerequisite to address this challenge, which is currently limited by the scarcity of experimental models. Here, we aimed at establishing and characterizing new patient-derived organoids xenograft (PDOX) models of advanced PCa. Materials & methods: We used two patient-derived organoid lines (PDOs), previously generated in our laboratory. P20-11 PDOs were derived from a lung metastasis obtained from a patient with hormone-naïve PCa. P20-23 PDOs were derived from a transurethral prostate resection obtained from a patient with metastatic castration-resistant PCa, previously treated with goserelin, docetaxel, and enzalutamide. PDOX were generated by subcutaneous injection of PDOs in NOD scid gamma (NSG) male mice. Organoids were derived from the PDOX tumors (PDOX-O). Matched patients’ tumor, PDOs, PDOX and PDOX-O samples were characterized using immunohistochemistry (IHC), immunofluorescence (IF), and whole exome sequencing (WES). Organoids were treated with different concentrations of drugs and cell viability was measured using CellTiter-Glo 3D, after a 5-day long treatment. Results: P20-11 PDOs developed tumors in 2 out of 6 mice, 10 months after injection. IHC analysis highlighted a loss of PTEN expression, overexpression of ERG and P53, as well as strong AR and NKX3.1 expression in the tumor, PDOs, PDOX and PDOX-O samples. WES analysis uncovered mutations in CTNNB1, PTEN and TP53 in all samples, and approximately 87% of shared non-synonymous mutations between the PDOX and the original patients’ tumor. Similar to the original PDOs, P20-11 PDOX-O displayed androgen sensitivity in vitro. P20-23 PDOs formed tumors in 3 out of 3 mice 8 months following injection. IHC and IF analyses highlighted a strong expression of CK8, PSMA, AR and NKX3.1, as well as a loss of PTEN expression in the tumor, PDOs, PDOX and PDOX-O samples. WES identified a pathogenic mutation in the PCa-associated gene ZMYM3 in all samples, associated with loss of protein expression. The activating AR point mutation L702H, previously linked to AR signaling inhibitors resistance, was detected in the tumor and in 2 out of 3 PDOX and their derived organoids. Overall, an average of 80% of non-synonymous mutations were shared between the patients’ tumor and PDOX. Finally, P20-23 PDOX-O did not respond to docetaxel or enzalutamide but exhibited sensitivity to the PI3K/AKT inhibitor ipatasertib. Conclusion: We have successfully generated two novel PDOX models, which highly resemble the original patients’ tumor and can be further cultured as organoids. These models are representative of relevant clinical and molecular subtypes of advanced PCa, providing further opportunities for translational studies. Citation Format: Raphaëlle Servant, Zoi Diamantopoulou, Michele Garioni, Luca Roma, Tatjana Vlajnic, Arnoud J. Templeton, Heike Pueschel, Salvatore Piscuoglio, Nicola Aceto, Helge Seifert, Cyrill A. Rentsch, Bubendorf Lukas, Clémentine Le Magnen. Establishment and characterization of two novel patient-derived organoid xenograft models of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3085. |
