Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response.
BACKGROUND
In vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments.


METHODS
Three PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA).


RESULTS
We compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors.


CONCLUSIONS
Ex vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.
['Zhang|Wenhao|W|', 'van Weerden|Wytske M|WM|', 'de Ridder|Corrina M A|CMA|', 'Erkens-Schulze|Sigrun|S|', 'Schönfeld|Edgar|E|', 'Meijer|Titia G|TG|', 'Kanaar|Roland|R|', 'van Gent|Dik C|DC|', 'Nonnekens|Julie|J|0000-0002-9644-7522']
D059002:Androgen Receptor Antagonists D000818:Animals D017209:Apoptosis D024682:BRCA2 Protein D001549:Benzamides D049109:Cell Proliferation D004260:DNA Repair D006801:Humans D008297:Male D051379:Mice D008819:Mice, Nude D009154:Mutation D009368:Neoplasm Transplantation D009570:Nitriles D010669:Phenylthiohydantoin D010793:Phthalazines D010879:Piperazines D000067856:Poly(ADP-ribose) Polymerase Inhibitors D011471:Prostatic Neoplasms D011944:Receptors, Androgen D046509:Tissue Culture Techniques D023041:Xenograft Model Antitumor Assays
prostate cancer tissue slices enzalutamide olaparib ex vivo culture