Abstract B084: Development of 3D organoid models from patient-derived conditionally reprogrammed cells in pancreatic cancer

Abstract Background: Pancreatic cancer is a highly lethal malignancy with limited therapeutic responsiveness. Despite recent advances, systemic chemotherapy remains the standard treatment for over 80% of patients, in the absence of established biomarkers to guide drug selection. Conventional two-dimensional (2D) culture models inadequately replicate the tumor microenvironment, underscoring the need for more physiologically relevant platforms such as three-dimensional (3D) organoid models. Methods: We established 3D organoid cultures from patient-derived conditionally reprogrammed cells (CRCs), which were initially propagated under 2D conditions. The 3D CRC organoids were developed using a Matrigel-based matrix without the addition of organoid-specific medium components, aiming to preserve the cells’ intrinsic molecular subtypes. We conducted morphological, molecular, and drug sensitivity analyses to compare the performance of the 3D CRC organoids with their 2D counterparts and clinical treatment outcomes. Results: The 3D CRC organoids retained the molecular features and mutational landscapes of their parent CRCs and exhibited distinct morphologies reflective of tumor stage and differentiation. Drug response profiling to gemcitabine plus nab-paclitaxel (Abraxane) and FOLFIRINOX showed that the 3D organoids more faithfully recapitulated patient clinical responses than the 2D models. Notably, the 3D organoids exhibited higher IC50 values, consistent with the enhanced structural complexity and drug penetration barriers characteristic of in vivo tumors. Conclusion: Matrigel-based 3D organoid culture systems offer a robust and clinically relevant platform for preclinical drug evaluation, addressing key limitations of conventional 2D models. While more resource- and time-intensive, the integration of 2D and 3D models enables efficient drug screening and validation. This strategy holds significant potential for biomarker discovery and advancing precision oncology in pancreatic cancer. Citation Format: Galam Leem, Jin Su Kim, Seungmin Bang. Development of 3D organoid models from patient-derived conditionally reprogrammed cells in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B084.