Abstract B20: Ex vivo prostate cancer organ culture: Development and validation of an experimental model system to test novel targeted therapies in prostate cancer and offer a patient-tailored approach

Abstract

Abstract Introduction: There is no cure for metastatic prostate cancer and novel targeted therapies are urgently required to improve survival and offer a patient-tailored approach. The purpose of this study is to validate the ex vivo organ culture model system of clinical human prostate cancers from patients for analysis of the effects of novel therapeutic agents in prostate cancer. In the studies presented here, we exploited ex vivo organ cultures to target the Jak2-Stat5a/b signaling pathway by a pharmacologic inhibitor of Stat5a/b IST5-002 in clinical prostate cancers. Development and validation of this ex vivo organ culture system may provide a more physiologic preclinical model than cell cultures or xenograft tumors to establish the efficacy of various novel targeted therapies and provide information on the probability of a drug's overall success in advancing through the drug development stages. In addition, ex vivo organ cultures may provide a tool to identify patients specifically sensitive to a given targeted therapy. Experimental Procedures: Organ cultures of prostate cancers from 10 patients undergoing radical prostatectomy were started within 2 hours of surgery. Tissue explants were cultured in a medium containing the pharmacologic inhibitor of Stat5a/b IST5-002 or the control at various concentrations starting at 10 µM for 7 days and analyzed for viability by hematoxylin-eosin staining and “in situ DNA end-labeling” assay. Stat5a/b activation was analyzed by immunohistochemistry for phosphorylated and nuclear Stat5a/b. In addition, qPCR was performed for the downstream target genes of Stat5a/b. Results: The overall morphology of malignant human prostate was well maintained in all the ten ex vivo organ cultures. All the prostate cancers analyzed by organ cultures in this study showed an effective dose-dependant drug response to the pharmacologic inhibitor of Stat5a/b by decreased Stat5 phosphorylation and downregulation of Stat5-target genes in cultured prostate cancers demonstrating the inhibitory effect of IST5-002 on the Jak-Stat5a/b signaling pathway. The minimum dose of the IST5-002 found to be effective was 25µM Conclusions: The pharmacologic inhibitor of Stat5a/b, IST5- 002 shows promising preclinical activity in clinical prostate cancers demonstrated by 3D-ex vivo organ cultures of clinical human prostate cancers as the experimental model system and would be a promising drug for use in a phase I clinical trial. Ex vivo organ culture system may serve as a tool to analyze the effects of various novel targeted therapies in human prostate cancer to supplement the data obtained from prostate cancer cell lines, and xenograft prostate tumors. Finally, the use of ex vivo prostate organ cultures from individual patients may help to select those patients who would respond to a given targeted therapy providing a patient-tailored approach. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B20.