Preclinical Models of Prostate Cancer: Patient-Derived Xenografts, Organoids, and Other Explant Models

Abstract

Prostate cancer remains a lethal disease. Preclinical cancer models that accurately represent the tumors of the patients they are intended to help are necessary to test potential therapeutic approaches and to better translate research discoveries. However, research in the prostate cancer field is hampered by the limited number of human cell lines and xenograft models, most of which do not recapitulate the human disease seen in the clinic today. This work reviews the recent advances in human patient-derived xenograft, organoid, and other explant models to address this need. In contrast to other tumor streams, the prostate cancer field is challenged by this approach, yet despite the limitations, patient-derived models remain an integral component of the preclinical testing pathway leading to better treatments for men with prostate cancer.

Figure 1.

Common patient-derived prostate cancer models for research discovery and translation. Patient-derived models are established from human prostate cancer tissue, either from the prostate or metastatic sites. From radical prostatectomy specimens, benign tissue can also be obtained, but these samples are not routinely used for patient-derived models. Cancer tissues are cut into small pieces either manually or by precision cutting. Tissue pieces or slices are then prepared for patient-derived xenografts (PDXs; often including supportive mesenchyme), patient-derived explants (PDEs; grown on gelatin sponges), or patient-derived organoids (PDOs; grown in 3D culture with dissociated cells). In addition to fresh primary specimens, PDE and PDO experiments can also be performed using PDX-derived tissues, expanding the capability of the models by allowing long-term propagated tumors to be studied in a high-throughput manner. Alternatively, PDOs can be transplanted back into mice to be grown as PDXs, allowing long-term growth in vivo.

Figure 2.

Human specimens for patient-derived models are acquired at specific stages of progression and can include localized or advanced metastatic disease. Localized, castrate-sensitive prostate cancer is most commonly obtained from radical prostatectomy specimens. Advanced prostate cancer tissues can be obtained from palliative resection for locally recurrent disease or at metastatic sites either by biopsy or tissue collection at autopsy; the latter samples represent metastatic castration-resistant prostate cancer (mCRPC). For studies in which the patient-derived specimens are taken at one time only, it is important to frame the question around this stage and not another one subsequent or prior. Although it is more challenging, the use of longitudinal specimens for modeling is even more desirable and can provide unique patient-based (personalized) information. TURP, Transurethral resection of the prostate.

Figure 3.

Patient-derived xenograft (PDX)-clinical trial (PCT) design showing how the PDX-derived tumor is sliced, engrafted, and divided among mouse treatment groups. The technique involves precision slicing of PDX tissue and regrafting of contiguous slices across all recipient mice, noting the numerical order of each slice and its position. For each drug treatment, a minimum of 10 mice is required (five vehicle + five controls). Tumors are regrown and mice are treated with vehicle/drug and harvested for analyses.