Abstract Background: Aggressive variant prostate cancers (AVPC) are a poorly understood subset of prostate cancers characterized by high mortality and extensive molecular heterogeneity. To address a lack of AVPC representative models for investigating underlying molecular and physiological mechanisms, we established NCI-LYM-1, a novel AVPC organoid/patient derived xenograft (PDX) derived from a patient with metastatic prostate cancer with small cell morphology displaying a unique clinical history and defined genomic features. It was hypothesized that this model would be able to accurately characterize biological underpinnings of the patient’s tumor profile and allow for comparative analysis to similar prostate cancers. Methods: NCI-LYM-1 was developed from a patient-derived AR-negative, ASCL1/Synaptophysin (SYP) -positive lymph node metastasis with small cell morphology. Short-read whole-genome sequencing (WGS) was used to identify genomic alterations and long-read WGS was used to identify epigenetic modifications. RNA-seq was used to characterize gene expression profiles. The resulting genomic, epigenetic, and transcriptomic data from NCI-LYM-1 was compared to molecular profiles from the LuCaP series of PDX models. In-vitro drug sensitivity assays were also conducted using organoid cultures. Results: NCI-LYM-1 harbored biallelic inactivation of known neuroendocrine prostate cancer (NEPC) drivers: PTEN, TP53, RB1 and BRCA2, in concordance with patient diagnostic history. In addition, epigenetic evidence supported a consistent phenotype between NCI-LYM-1 and the donor tumor, including greater gene expression of neuroendocrine marker ASCL1 with decreased AR expression. Comparisons between NCI-LYM-1 and LuCaP models further supported transcriptional similarities between the model and a subset of AVPC cancer subtypes. Drug sensitivity assays were also consistent with the patient’s prior treatment exposure, displaying PARP inhibitor sensitivity but a lack of sensitivity to platinum treatments. Conclusions: NCI-LYM-1 faithfully recapitulates the phenotypic and genomic characteristics of aggressive metastatic AVPCs, including the display of neuroendocrine features. NCI-LYM-1 will be a useful model system to study molecular frameworks of understudied cancers like those of AVPC, including aspects such as drug sensitivity, disease progression, and lineage plasticity. Citation Format: Ana S. Jaramillo, Chennan Li, JuanJuan Yin, Melissa L. Abel, Dana S. Vargas, Kinjal Bhadresha, Sumeyra Kartal, Joseph Twohig, Tri M. Truong, Anish Thomas, Cindy H. Chau, Kathleen Kelly, William D. Figg, Adam G. Sowalsky. NCI-LYM-1 molecularly and phenotypically recapitulates aggressive variant prostate cancer 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 (2Suppl): Abstract nr A025.
Jaramillo et al. (Tue,) studied this question.