Abstract A023: Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications

Abstract Patient-derived organoids (PDOs) have emerged as a powerful tool for modeling human cancers due to their ability to closely mirror in vivo architecture and preserve the genetic landscape of tumors. They offer a crucial platform for studying disease progression and treatment responses. In this study, we present a comprehensive characterization of a unique collection of PDO cultures derived from pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy often diagnosed in advanced stages with limited treatment options and poor prognosis. Our investigation explores morphological and genetic profiling of 10 PDAC PDOs, specifically identifying distinct drug-response patterns. The morphological characteristics of these PDO cultures were investigated by microscopy, while the mutational status was acquired by panel sequencing. Subsequently, PDOs were treated with a panel of 10 inhibitors, either individually or in combination. The response to these treatments was assessed through live-cell imaging (Incucyte®) to capture and quantify changes in organoid morphology and endpoint measurements of cellular viability using a CellTiter-Glo® assay. Our detailed in vitro drug sensitivity testing revealed a remarkable diversity in the responses of the PDAC PDOs to different chemotherapeutic agents, including those currently under clinical trials. Of notable significance is the depth of understanding we have achieved, allowing us to establish potential correlations between PDO morphology, genetic mutations, and drug reactions. This finding provides a key insight into the complex interplay of these factors and their impact on treatment outcomes, offering valuable insights into understanding individual tumor subtypes' sensitivity or resistance to treatments. The PDOs exhibited a spectrum of cancer-associated mutations, including KRAS, TP53, SMAD4, CDKN2A, and ARID1A, reflecting the heterogeneity observed in PDAC patients. Morphologically, the organoids displayed various growth patterns, ranging from cystic and regular structures to filled or unfilled, granular, dark, and light membrane structures. Drug treatments underscored the diverse and unique drug-response profiles within the PDOs, with some demonstrating sensitivity to multiple treatments. In contrast, others exhibited resistance, highlighting the intricate nature of drug responses within this model. Overall, our findings emphasize the ability of PDAC organoids to faithfully capture the complexity and heterogeneity of the disease, making them promising platforms for guiding personalized oncology approaches. The diverse drug response profiles observed in PDOs advocate leveraging this model to develop precision medicine strategies tailored to patients' characteristics, ultimately paving the way for more effective and personalized treatment regimens in the fight against PDAC. Citation Format: Constanza Tapia Contreras, Günter Schneider, Denise Müller, Kimia Mirzakhani, Karly Conrads, Silke Kaulfuß, Tim Beißbarth, Gabriela Salinas, Nils Beyer, Sophia Reinländer, Ulrix Sax, Elisabeth Heßmann, Volker Ellenrieder, Philipp Ströbel, Michael Ghadimi. Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr A023.