Abstract LB-A18: Targeting the WNT-pathway in 3D-cultured in vitro PDX models for pancreas cancer

Abstract

Abstract Creating patient-derived xenograft (PDX) models from human cancers allows bio-banking, propagation, characterization and drug testing on a large panel of tumor variants. To scale up the number of compound tests, identify relevant compound doses, increase the throughput, and study relevant cancer-driving pathways we developed 3D in vitro culture methods for PDX model-derived cell isolates. In this effort, each individual model is subjected to a wide panel of culture medium formulations, amongst which some media contain WNT-pathway stimulating components. We identified an absolute dependency of a pancreatic in vitro PDX tumor to the WNT-signaling potentiating factor R-Spondin, while other pancreas tumors showed little or no dependency. To further study the dependency of pancreatic PDX tumors on the functionality and signaling of the WNT-pathway, we exposed in vitro PDX cultures to increasing doses of anti-FZD7, anti-FZD8 and to the Porcupine inhibitor LGK974, which blocks WNT palmitoylation and therefore secretion. Our findings are that the WNT-pathway is functional and contributing to pancreas cancer outgrowth and morphological differentiation to different extents in different patient-models. Our in vitro PDX culture system in combination with 3D phenotypic analysis allows in-detail study of the WNT-pathway, as well as by supplementation or omission of secreted factors, addition of small molecule inhibitors and by exposure to antibodies. These in vitro PDX models can be used to test novel compounds and antibodies targeting the WNT-pathway and underscore the WNT-pathway as a potential target in pancreatic cancer. Citation Format: Thomas Dijkmans, Bram Herpers, Sander Basten, Kuan Yan, Torsten Giesemann, Julia Schueler, Leo Price. Targeting the WNT-pathway in 3D-cultured in vitro PDX models for pancreas cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A18.