Abstract 45: Patient-derived 3D tumor cultures for compound screening and pre-clinical drug development

Abstract

Abstract Patient-derived xenograft (PDX) models from human cancers allow propagation, characterization and drug testing on a large panel of tumor variants. To expand the potential of these human-relevant PDX models, we sought to develop 3D ex vivo culture methods for PDX-derived tumor cells that show in vivo-like growth characteristics such as polarization and invasion, and allow measurement of response to therapeutics. By embedding dissociated PDX material in extracellular matrix enriched hydrogels we generate ex vivo cultures that form organotypic 3D tissues driven by relevant interaction with the stromal microenvironment in 384 well plates. Our automated high content screening platform with image analysis powered by OMiner software is used to measure morphologic features of the microtissues. This combination creates a unique high throughput ex vivo PDX screening platform that not only allows efficient profiling drug of responses and quantify tumor spheroid volume, apoptosis and tumor invasion, but also enables selection of the optimal PDX tumor models for subsequent validation of candidates in vivo. Results Hydrogel and growth media composition were optimized to support growth of tumor tissues in vitro from cells derived from various tumor indications, including breast, pancreas, colon, melanoma, and lung cancer PDX tumors. Tumor tissues were cultured in a 384-well format and used to test standard of care chemotherapeutics (e.g. cisplatin, 5-Fu), small molecules (e.g. lapatinib, paclitaxel), and antibodies/ADCs (Trastuzumab, T-DM-1). High content 3D image analysis and data analysis generates a tumor model specific drug profile, reporting therapeutically relevant responses such as cell growth, killing and invasion. These responses serve as a benchmark allowing comparison to novel and experimental drugs, as well as responses across tumors with different mutation profiles. We identified an absolute dependency of a pancreatic PDX model to the WNT-signaling pathway potentiator R-spondin. This allows specific stimulation and targeting of a pathway that is particularly relevant in the development pancreatic cancer. Conclusions In contrast to organoid cultures, short-term ex vivo culture of tumor captures the heterogeneity of the primary tumor as well as enabling access to large collections of well-characterized tumors. We established several PDX model-derived 3D tumor cultures in which standard-of-care, targeted therapies and novel therapeutic agents against specific pathways can efficiently be screened, based on therapeutically relevant parameters and their changing morphological profile. This method enables both the ex vivo selection of drug candidates in a pre-clinical setting as well as efficient selection of PDX models for in vivo follow-up in the same tumor. This highly translational in vitro-in vivo PDX pipeline is expected to reduce attrition and increase efficiency in early drug-discovery. Citation Format: Sander Basten, Bram Herpers, Kuan Yan, Julia Schueler, Leo S. Price. Patient-derived 3D tumor cultures for compound screening and pre-clinical drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 45.