Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

Abstract

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.

Role of the DNA damage response in prostate cancer formation, progression and treatment

“…Besides blood-based germline mutation and biopsy based somatic mutation testing, new studies are looking into circulating tumor cells (CTC) or cell-free DNA based detection of a panel of clinically actionable genes to select eligible patients [90,94,95]. Moreover, the efforts made for identifying tumors with HR deficiency by using mutational signatures (HRDetect) or functional HRD tests will guide us to a more personalized cancer management approach [96][97][98][99][100].…”

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

“…Both EGFR and BIRC5 are highly expressed in basallike PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC. therefore suitable models for studying tumor biology and drug response, both in vivo and ex vivo/in vitro [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Using this approach, we have generated a dataset that can be used to quickly assess and compare responses of breast cancer PDXs of varying subtypes to many different drugs, most of which are approved by the U.S. Food and Drug Administration (FDA) for various cancer or non-cancer indications.…”

PDX: Moving Beyond Drug Screening to Versatile Models for Research Discovery

“…PDXs tissues are useful for optimizing these protocols because they provide a consistent and abundant supply of the same tumors. Indeed, PDX tissue was used to identify culture conditions and growth media for maximizing the proliferation of prostate cancer cells in explants [ 48 , 55 ]. Similarly, digested PDX tissues were used to compare the growth of prostate cancer organoids in numerous different formulations of media, showing that modified media improved the growth of some tumors [ 47 ].…”

“…For example, in prostate cancer research explants are usually limited to primary patient tumors because it is more challenging to obtain sufficient tissue from metastases, whereas organoids are limited to cells from metastases because cultures of primary tumors often become contaminated with benign epithelium [ 42 , 56-58 ]. In both cases, PDXs may provide a way to select the most suitable tumor for a study, one that represents the desired pathology, genomic features, and stage of disease progression [ 21 , 47 , 48 ].…”