Widespread reduction to practice of genetically engineered mouse (GEM) cancer models for predictive cancer drug efficacy evaluation is largely impeded by significant costs and the extensive expertise required to develop and utilize GEM models in well-powered and controlled studies. Our objective in this project is to develop libraries of ES and iPSC lines derived from well characterized and clinically relevant GEM models such that the complex breeding of GEM cancer models is bypassed, thus streamlining the production of experimental cohorts. The first goal is to derive banked ES cells from several cancer models that are validated for the production of tumor-bearing mice wherein the natural disease history is preserved. Second, we are examining the use of iPSC technology for production of such cohorts. To this end, we are applying adenoviral vector gene transfer technology to transiently express multicistronic stem-cell factors upon infection of genetically divergent pools of cells derived from fetal tissues of multi-allelic GEM models. The multi-lineage and tumor producing capacity of these cells will then be evaluated after the generation of chimeric mice as with those derived from ES cells. Thus far, we have validated ES cell establishment for a 4-allele GBM GEM model that develop GBMs which are indistinguishable from the initial germline model. Similar development of SEOC generating ES cells and chimeras is in progress.
