Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants

SIMPLE SUMMARY: There is a widespread push toward more biologically relevant pre-clinical models of prostate cancer that can improve the discovery and translation of new drugs and biomarkers for this disease. Patient-derived explant culture is an innovative pre-clinical model that utilizes surgical prostate cancer specimens in a way that retains the architecture, microenvironment and heterogeneity of prostate tumors—factors that critically influence cell behavior and response to therapy. With increasing tissue complexity comes increasing complexity of analysis. The aim of this study was to provide critical information for the successful application and analysis of the patient-derived prostate cancer explant model. ABSTRACT: Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.