(P 254) A COLLECTION OF PATIENT-DERIVED XENOGRAFT MODELS OF GASTROINTESTINAL STROMAL TUMORS

Objective: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancy of the gastrointestinal tract. Most GIST harbor gain-of-function mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) oncogenes, encoding for respective receptor kinases. Five tyrosine kinase inhibitors (TKI) are currently approved for treatment of advanced KIT- or PDGFRA-driven GIST. During TKI treatment most tumors develop secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet medical need for novel therapies. Patient-derived xenograft (PDX) models can be used for preclinical drug testing of new compounds in vivo. We recently expanded our established GIST PDX platform with new models with different molecular background.

Methods: Fresh tumor material was collected from consenting GIST patients who undergo surgery or diagnostic biopsy. A piece of the tumor tissue was transplanted subcutaneously on both flanks of partially immunodeficient, athymic NMRI nu/nu mice. Once tumor growth was observed, the tumor was re-transplanted to a next generation of mice (“passaging”). With every passage a piece of the tumor was collected; histopathological and molecular characteristics were compared with the characteristics from the original patient tumor.

Results: Since the launch of the XenoSarc platform in 2004 we have transplanted 149 tissue samples from 114 GIST patients, resulting in 12 established and well-characterized GIST models with different mutations and TKI sensitivity, and an additional 15 models in early stage (passage ≤2). All models have KIT or PDGFRA driver mutations. Three of these models harbor secondary mutations, of which two have a secondary mutation in KIT exon 17 and one in KIT exon 16. One model is characterized by an imatinib-resistant PDGFRA exon 18 p.D842V mutation.
Drug testing in selected models already provided the preclinical rationale and supportive evidence for a number of ongoing and completed clinical GIST trials for some approved and experimental compounds.

Conclusion: We are expanding our established platform of well-characterized GIST PDX models, that were proven to serve as an excellent tool for preclinical drug testing and tumor biology studies. The platform is available for cooperative projects with academic and commercial partners.