Ex vivo prostate cancer explant organ culture model system for targeted drug development in prostate cancer

Abstract

110 Background: Effective drug development does not always occur successfully in prostate cancer despite discovery of pathways and targeted agents due to lack of pre-clinical models that effectively mimic prostate cancer in humans. We optimized a novel Ex vivo organ-culture model system using clinical human prostate cancers to test novel therapeutic agents targeting the Jak2/Stat5a/b pathway in prostate cancer; this pre-clinical model may be useful to test novel drugs in prostate cancer for target validation and efficacy. Methods: Organ explant cultures of prostate cancers from 16 patients undergoing radical prostatectomy were performed within 2 hours of surgery, 1-2 mm fresh tissue explants were cultured in a medium containing different doses of pharmacologic inhibitor of Stat5a/b (IST5-002) or a small molecule Jak2 inhibitor with appropriate controls and treated with the drug daily for 7 days. Explants were fixed and analyzed for viability by hematoxylin-eosin staining and “in situ DNA end-labeling” assays, Stat5 activation was analyzed by immunohistochemistry for phosphorylated Stat5a/b. Results: Morphology of prostate cancer was well maintained and dose-dependent tumor responsesoccurred with the Stat5a/b and Jak2 inhibitors. The minimum effective dose of each drug was 25 micromoles and considerable effects on morphology and apoptosis were seen at 50 micromoles. Conclusions: Inhibition of the /Stat5a/b pathway showed promising preclinical activity in prostate cancer as demonstrated by our 3D-ex vivo explant organ culture model system using clinical human prostate cancers, corroborating the data from prostate cancer cell lines and xenograft prostate tumors. This model system may also serve as an effective pre-clinical tool to explore new targets and analyze the effects of different targeted therapies in prostate cancer. Finally, since this uses Ex vivo prostate cancer explants from individual prostate cancer patients, once could test different targeted agents in parallel and based on the efficacy of individual drugs, select patients who would best respond to a particular drug, thus providing an effective personalized medicine approach.