Abstract IA006: A framework for early interception of prostate cancer lineage plasticity

Abstract Neuroendocrine prostate cancer (NEPC) can arise from prostate adenocarcinoma (PRAD) through lineage plasticity as a resistance mechanism to androgen blockade. NEPC is aggressive and often diagnosed when patients are not fit for additional intensive treatment. Several blood biopsy approaches have demonstrated promise for detecting NEPC based on its epigenomic signatures. Here, we tested the hypothesis that epigenomic blood biopsy can detect lineage plasticity – and the associated upregulation of targetable cell-surface proteins – before NEPC is diagnosed on a tumor biopsy. We tested plasma samples from a retrospective cohort of patients with prostate cancer who developed NEPC on treatment (N=17 individuals, N=87 timepoints). Using cell-free ChIP-seq, we quantified signatures of NEPC and PRAD based on circulating histone modification profiles. This approach allowed us to quantify relative amounts of NEPC-derived vs. PRAD-derived chromatin, which were often both detected in plasma in the setting of lineage plasticity. In five cases, neuroendocrine signatures were detectable in plasma before NEPC diagnosis, with an average lead-time of 48 days (range 11-74 days). Further, circulating H3K4me3 – a histone modification enriched at active gene promoters – identified targetable cell surface proteins that are upregulated in NEPC, such as DLL3 (AUROC of 0. 96 for distinguishing DLL3 IHC-positive vs. negative tumors across 11 patients). These observations support the possibility of detecting lineage plasticity early using blood-based monitoring of high-risk patients and will enable the testing of early interception strategies. Citation Format: Garyoung Gary Lee, Rashad Nawfal, Karl Semaan, Marc Eid, Razane El Hajj Chehade, Elio Ibrahim, Ze Zhang, Gunsagar Gulati, Wassim Daoud, Gaelle Nafeh, Katelyn Kuczmarski, Hailey Stoltenberg, Rachel Trowbridge, Gwo-Shu Mary. Lee, Ji-Heui Seo, Mark Pomerantz, Matthew L. Freedman, Sylvan C. Baca. A framework for early interception of prostate cancer lineage plasticity 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 IA006.