Abstract 1461: A panel of patient derived gastrointestinal stromal tumors (GIST) xenograft models for in vivo preclinical drug testing

Abstract

Abstract Objective: Most GIST are dependent on the KIT/PDGFRA signaling pathway and therefore can be treated with specific tyrosine kinase inhibitors (TKI). With time GIST develop resistance to TKI. We need reliable models which can be used for preclinical drug testing. Methods: Patient-derived xenografts were established in nu/nu NMRI mice by subcutaneous implantation of fresh, surgically resected tumor specimens from consenting patients with GIST treated at the University Hospitals Leuven. Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of mice. At each passage tumor fragments were collected for histological and molecular characterization. A model was considered to be established after observing stable histological and molecular features for at least two passages. Results: At present we have access to five successfully established GIST models, with different KIT mutations and different sensitivity to standard TKI (Table). Untreated tumors from subsequent passages show morphological and immunohistochemical features resembling the original patient biopsy, verifying the stability of GIST xenografts growth. KIT mutational status has also been confirmed in samples obtained from all models. These models are used for pre-clinical testing of new therapeutic approaches, and current results served as a rationale for at least four prospective clinical trials. If needed, we parallel our patient-derived models with in vitro or in vivo studies using one of the few established GIST cell lines. Conclusion: Our established GIST xenografts maintain the histological and molecular characteristics of the original patient sample and are a very useful and reliable preclinical platform for testing the new targeted approaches in GIST. The platform is available for collaboration with academic and commercial partners (contact patrick.schoffski@uzleuven.be). The overview of patients-derived GIST xenograftsModel*KIT mutationIn vivo efficacy [% of relative tumor volume after three weeks]PrimarySecondaryImatinib (50mg/kg, BID)Sunitinib (40mg/kg, QD)UZLX-GIST1p.V560Dn/a2020UZLX-GIST2p.A502_Y503dupn/a17080UZLX-GIST3p.W557_V559delinsFn/a2525UZLX-GIST4p.K558_G565delinsRn/a4520UZLX-GIST9p.P577delp.W557LfsX5, p.D820G250170*models which showed tumor growth for at least two passages; n/a-not applicable Citation Format: Agnieszka Wozniak, Thomas Van Looy, Giuseppe Floris, Yemarshet K. Gebreyohannes, Jasmien Wellens, Haifu Li, Jasmien Cornillie, Ulla Vanleeuw, Daphne Hompes, Marguerite Stas, Maria Debiec-Rychter, Raf Sciot, Patrick Schoffski. A panel of patient derived gastrointestinal stromal tumors (GIST) xenograft models for in vivo preclinical drug testing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1461. doi:10.1158/1538-7445.AM2015-1461