Abstract Patient-derived xenograft (PDX) and organoid (PDO) models provide platforms to study prostate cancer (PCa) progression and therapy, especially in underrepresented populations. Here we report the first de novo neuroendocrine prostate cancer (NEPC) from a consented patient of African Ancestry with localized disease and no prior treatment before radical prostatectomy. African American patient had a pTN2 tumor, Gleason7 (4+3) and PSA or 3.6. Acquired tissue was collected for PDX and PDO establishment as well as for downstream molecular characterization. To uncover genetic drivers of aggressive phenotypes, we performed whole exome sequencing on DNA from the primary tumor and the established PDX using the Illumina Exome Kit and Twist Biosciences Exome Panel 2.0, followed by bioinformatic analysis. Computational workflows using Nextflow, including nf-core/sarek, identified somatic single nucleotide polymorphisms (SNPs), mutations (Mutect2, Strelka), and copy number variations (CNVs) (CNVkit, Control-FREEC). Variant annotation with Variant Effect Predictor and SnpEff linked variants to cancer progression. Analysis of the tumor samples revealed CNAs and mutations in genes similar to those seen in previously published NEPC. Protein expression by western blot and IHC identified altered protein expression peculiar to the NEPC phenotype further validating our primary tissue and its derived PDX models to have the NEPC phenotype. Furthermore, novel markers identified provide insight into molecular drivers of this prostate cancer phenotype and may inform targeted therapies for high-risk localized PCa. Citation Format: Diana Rodriguez, Surendra Gulla, Tej Sharma, John Bodkin, Roberto Pili, John E. Tomaszewski, Remi M. Adelaiye-Ogala. Targeted genetic profiling of a de novo neuroendocrine patient-derived xenograft (PDX) and organoid model of prostate cancer from patient with African Ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1283.