1434P - A panel of gastrointestinal stromal tumours (GIST) xenograft models for in vivo preclinical drug testing

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Cancer Biology
GIST
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Agnieszka Wozniak
Citation Annals of Oncology (2014) 25 (suppl_4): iv494-iv510. 10.1093/annonc/mdu354
Authors A. Wozniak1, T. van Looy1, G. Floris2, Y.K. Gebreyohannes1, J. Wellens1, H. Li1, J. Cornillie1, U. Vanleeuw1, D. Hompes3, M. Stas3, M. Debiec-Rychter4, R. Sciot5, P. Schöffski1
  • 1Laboratory Of Experimental Oncology, Department Of Oncology And Department Of General Medical Oncology, KU Leuven and University Hospitals Leuven, 3000 - Leuven/BE
  • 2Department Of Patholgy, KU Leuven and University Hospitals Leuven, 3000 - Leuven/BE
  • 3Department Of Surgical Oncology, University Hospitals Leuven, 3000 - Leuven/BE
  • 4Department Of Human Genetics, KU Leuven and University Hospitals Leuven, 3000 - Leuven/BE
  • 5Department Of Pathology, KU Leuven and University Hospitals Leuven, 3000 - Leuven/BE

Abstract

Aim

Most GIST are dependent on the KIT/PDGFRA signalling pathway and therefore can be treated with specific tyrosine kinase inhibitors (TKI). With time GIST develop resistance to the 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 tumour specimens from consenting patients with GIST treated at the University Hospitals Leuven. Once tumour growth was observed, pieces of tumour were re-transplanted to next generations of mice. At each passage tumour 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 TKIs (Table). Established GIST xenograft models and their sensitivity to standard treatment. In vivo efficacy was assessed by % of relative tumour volume after 3 weeks under either imatinib (50mg/kg BID) or sunitinib (40mg/kg QD)

Model* KIT mutation In vivo efficacy
Imatinib Sunitinib
UZLX-GIST1 p.V560D 20 20
UZLX-GIST2 p.A502_Y503dup 170 80
UZLX-GIST3 p.W557_V559delinsF 25 25
UZLX-GIST4 p.K558_G565delinsR 45 20
UZLX-GIST9 p.P577del; p.W557LfsX5; p.D820G 250 170

*models which showed tumor growth for at least two passages Untreated tumours from subsequent passages show morphological and immunohistochemical features resembling the original patient biopsy, verifying the stability GIST xenografts growth. KIT mutational status has also been confirmed in samples obtained from all models. These models are used for subsequent testing of new therapeutic approaches and current results have had an impact on 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.

Conclusions

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.

Disclosure

All authors have declared no conflicts of interest.