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Introduction: Castration-resistant metastatic prostate cancer is a lethal disease for which no curative therapies exist.Despite improved understanding of many pathways and potential agents active in prostate cancer, clinical translation of targeted drugs does not always occur due to lack of pre-clinical models that effectively mimic prostate cancer in humans.We developed an ex-vivo organ-culture model system using human prostate cancers to test novel therapeutic agents targeting the Jak2/Stat5a/b pathway in prostate cancer;this system may provide a more physiologic preclinical model than cell cultures or xenograft tumors to test novel drugs.Methods: Organ 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;they were treated with the experimental drug daily for 7 days.Explants were then 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: The overall morphology of malignant human prostate was very well maintained in all the 16 ex vivo organ cultures and all the organ cultures showed an effective dose-de pendent tumor response to both IST-002 and Jak2 inhibitor.The minimum dose of the IST5-002 and the Jak2 inhibitor found to be effective was 25 micromoles.Conclusions: Stat5 inhibition with a pharmacologic inhibitors of Jak2/Stat5a/b pathway showed promising preclinical activity in prostate cancer as demonstrated by our 3D-ex vivo organ culture model system using clinical human prostate cancers and these drugs can be further exploited in phase Ⅰ clinical trial.This model system may serve as an effective pre-clinical tool to explore new targetsand analyze the effects of different novel targeted therapies in prostate cancer to supplement the data obtained from prostate cancer cell lines and xenograft prostate tumors, which in turn might increase the chances of successful clinical drug development.Finally, the use of ex vivo prostate organ cultures from individual prostate cancer patients may help to select those patients who would respond to a given targeted therapy,thus providing an effective patient-tailored approach.