Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy

Abstract

BackgroundEffective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models.MethodsWe improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated.ResultsHigh-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans.ConclusionsOur study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC.

Intraductal carcinoma of the prostate can evade androgen deprivation, with emergence of castrate‐tolerant cells

“…Adenocarcinoma also regressed after androgen deprivation in these PDXs. This finding is similar to previous studies, where castrate-tolerant cells have been identified in other cohorts of PDXs from moderate-to high-grade tumours [17,20,21]. The residual tumour cells in IDC-P and adenocarcinoma are not yet castrate-resistant, as they do not proliferate autonomously in the absence of systematic androgens.…”

Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma

“…Organotypic cultures using 3D cultured tumor cells or live tissue slice have also been developed previously in evaluating clinical therapeutics (33-35). Most of tissue slice-based cultures and drug testing are in the format of 6-well or 24-well plate (36, 37), and tissue slice viability was measured with labor and time-intensive methods such as immunohistochemistry staining or western blotting, which are not applicable for large-scale drug testing (19, 27). In our system, the LTSA can be performed in a 96-well-plate format and allows testing drug sensitivity in 3-5 days objectively with a commercially available reagent, which will significantly reduce the time and resources compared to the test in animal models.…”

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

“…10 weeks), and well within the time frame required to modulate proliferation in PDX models. For example, changes in proliferation can be detected within 3 days after castration and 4 weeks after testosterone administration [28, 29], or after 1 week of other androgen-targeted agents, such as Enzalutamide (Taylor, unpublished data).…”