Patient-Derived Xenograft Models for Translational Prostate Cancer Research and Drug Development.

Abstract

Patient-derived xenografts (PDXs) are a valuable preclinical research platform generated through transplantation of a patient's resected tumor into an immunodeficient or humanized mouse. PDXs serve as a high-fidelity avatar for both precision medicine and therapeutic testing against the cancer patient's disease state. While PDXs show mixed response to initial establishment, those that successfully engraft and can be sustained with serial passaging form a useful tool for basic and translational prostate cancer (PCa) research. While genetically engineered mouse (GEM) models and human cancer cell lines, and their xenografts, each play beneficial roles in discovery science and initial drug screening, PDX tumors are emerging as the gold standard approach for therapeutic proof-of-concept prior to entering clinical trial. PDXs are a powerful platform, with PCa PDXs shown to represent the original patient tumor cell population and architecture, histopathology, genomic and transcriptomic landscape, and heterogeneity. Furthermore, PDX response to anticancer drugs in mice has been closely correlated to the original patient's susceptibility to these treatments in the clinic. Several PDXs have been established and have undergone critical in-depth characterization at the cellular and molecular level across multiple PCa tumor subtypes representing both primary and metastatic patient tumors and their inherent levels of androgen responsiveness and/or treatment resistance, including androgen-sensitive, castration resistant, and neuroendocrine PCa. Multiple PDX networks and repositories have been generated for the collaborative and shared use of these vital translational cancer tools. Here we describe the creation of a PDX maintenance colony from an established well-characterized PDX, best practice for PDX maintenance in mice, and their subsequent application in preclinical drug testing. This chapter aims to serve as a go to resource for the preparation and adoption of PCa PDX models in the research laboratory and for their use as a valuable preclinical platform for translational research and therapeutic agent development.