Abstract A002: From reconstruction to resolution: platform approaches to engineer the prostate cancer phenoscape and map its evolution

Abstract Understanding how prostate cancers evolve toward treatment resistance requires experimental systems that both recreate the phenotypic diversity of the disease and resolve lineage dynamics at high resolution. We developed complementary platforms to meet these challenges. The Prostate Mouse Platform (ProMPt) is a genetically scalable organoid- and allograft-based system encompassing over 150 combinatorial genotypes, enabling reconstruction of the principal phenotypic states of prostate cancer, from androgen-responsive tumors to castration-resistant double-negative, hybrid/mixed, and neuroendocrine-like variants. Through multi-omic and functional analyses, ProMPt models capture the context-specific vulnerabilities that arise during adaptation to androgen deprivation or growth-factor loss. To map and track this evolving phenoscape, we designed XCODE, a universal, multiplatform barcoding technology that enables clonal tracing across sequencing-, cytometry-, and imaging-based modalities (CyTOF, Phenocycler, Xenium). XCODE integrates lineage information across bulk, single-cell, and spatial layers, linking histology, clonal dynamics, phenotype, and microenvironmental context. Together, ProMPt and XCODE provide a powerful preclinical framework to reconstruct, resolve, and perturb tumor evolution within a controlled yet clinically relevant landscape. This integrated approach reveals how defined genetic combinations reshape lineage plasticity, signaling networks, and therapeutic responses, exposing new intervention points to prevent or redirect adaptive evolution in advanced prostate cancer. Citation Format: Marco Bezzi. From reconstruction to resolution: platform approaches to engineer the prostate cancer phenoscape and map its evolution [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 A002.