Abstract B080: A patient-derived metastasis model with spontaneous neuroendocrine transformation

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, in which patients each carry distinct molecular features that drive metastatic progression. However, the lack of clinically representative models that recapitulate this disease have limited our understanding in the heterogeneity between patients. LuCaP 147, established from a liver metastasis biopsy, is a prostate cancer transplantable xenograft carrying AR and SPOP mutations with a further hypermutated phenotype, as well as loss of MSH2 and MSH6 expression. Methods: Using LuCaP 147, we developed a novel patient-derived metastasis (PDM) model in NSG mice via intracardiac injection. The development of metastasis was monitored through weekly bioluminescent imaging. We analyzed the tumor burden and survival rate of the PDM147 models. At the endpoint, long bones, spines and soft tissues were collected. To evaluate the histologic phenotype of PDM147, tissue sections were stained by immunohistochemistry (IHC) for adenocarcinoma markers including AR and neuroendocrine markers (which include SOX2, ASCL1, and SYP). Results: After intracardiac injection, tumor burden (BLI) was detected after 5 weeks, and mice developed morbidity after 7-8 weeks. H&E stains showed that PDM147 developed bone metastases in spines, long bones, as well as visceral metastases in liver, brain, spinal cord, kidney and adrenal glands. IHC indicated that metastases were heterogeneous with both AR+/NE- and AR-/NE+ cells. AR+ and SYP+ cells were intermingled in the tumor, but the stains themselves were mutually exclusive between cels. Interestingly, no androgen-deprivation therapy was needed to promote NE differentiation, showcasing the biological novelty [SA([1] of this model. Conclusion: PDM147 is a hypermutated tumor with mutually exclusively expressing AR+ and NE+ markers in metastatic sites, including soft tissues and nervous tissues. Future work to define distinct pathways and molecular markers that lead to de novo vs. treatment-induced NE phenotype may offer a better understanding of the biology driving metastatic spread in these similar yet distinct NE subtypes and the role a hypermutator tumor can have in prostate cancer progression. These findings underscore the value of patient-derived models to study mCRPC progression and heterogeneity. Further use of these models for high-throughput drug screens may uncover targeted therapies for advanced prostate cancer. Citation Format: Dana S. Vargas Solivan, JuanJuan (Ivy) Yin, Tri Truong, Joseph Twohig, Ross Lake, Adam G. Sowalsky. A patient-derived metastasis model with spontaneous neuroendocrine transformation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B080.