New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 151-151
Author(s):  
Mitchell Lawrence ◽  
David Clouston ◽  
Mark Frydenberg ◽  
Declan G. Murphy ◽  
Carmel Jo Pezaro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ex Vivo ◽  
Castration Resistant Prostate Cancer ◽  
Preclinical Testing ◽  
Novel Treatments ◽  
Nsg Mice ◽  
Treatment Naïve ◽  
Castrate Resistant ◽  
Rapid Autopsy

151 Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.

Leveraging RB status to define therapy for castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 96-96
Author(s):  
Renee de Leeuw ◽  
Clay de Comstock ◽  
Daniela de Pollutri ◽  
Matthew Joseph Schiewer ◽  
Stephen J Ciment ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Tissue Samples ◽  
Ki67 Staining ◽  
Cell Architecture ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

96 Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.

scholarly journals Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1167-1179
Author(s):  
David R. Wise ◽  
Jeffrey A. Schneider ◽  
Joshua Armenia ◽  
Victor Adorno Febles ◽  
Bridget McLaughlin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Nk Cells ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dkk1 Expression ◽  
Rapid Autopsy ◽  
Dickkopf 1

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

A novel small molecule inhibitor of p300/CBP for the treatment of castration-resistant prostate cancer: Preclinical evaluation.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 168-168 ◽  
Author(s):  
Nigel Brooks ◽  
Neil Pegg ◽  
Jenny Worthington ◽  
Barbara Young ◽  
Amy Prosser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Small Molecule ◽  
Binding Protein ◽  
Xenograft Model ◽  
Creb Binding Protein ◽  
Castration Resistant Prostate Cancer ◽  
Histone Acetyl Transferase ◽  
Castrate Resistant

168 Background: Targeted degradation of androgen receptor (AR) and androgen receptor variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators of AR. We have developed potent, selective and orally active small molecule inhibitors of the bromodomain of p300/CBP and investigated their role in regulating the expression and function of AR and ARV. Methods: Binding affinity to p300, CBP and BRD4 was measured in a surface plasmon resonance (SPR) assay and potency and functional activity was demonstrated in a panel of prostate cells lines representing hormone responsive (LNCaP), hormone independent (DU145, PC3) and castrate resistant disease (22Rv1, C4-2, VCaP, LNCaP-AR). Effects of p300/CBP inhibitors (and the BET inhibitor, JQ1), on AR, AR-V7 splice variant and c-Myc protein, as well as c-Myc, KLK3 and TMPRSS2 gene expression, were assessed in 22Rv1 cells in vitro. In vivoeffects on biomarkers were measured in a 22Rv1 xenograft model. Results: CCS1357, an in vitro probe compound, binds to p300 and CBP with high affinity (Kd=4nM) and selectivity (Kd=245nM; BRD4) and is a potent inhibitor of cell proliferation in castrate resistant cell lines (IC50=100nM in LnCaP-AR; 350nM in 22Rv1) with minimal effects in hormone independent lines. CCS1357 significantly down-regulated AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with JQ1 at equivalent proliferation IC50s. CCS1357 effects were reversed by the proteasome inhibitor, MG132. CCS1357 also caused a profound inhibition of c-Myc, KLK3 and TMPRSS2 genes measured by qPCR in 22Rv1 cells in vitro. A preclinical candidate (CCS1477) given as a single oral dose (30mg/kg) inhibited plasma PSA and tumour AR and AR-V7 in a 22Rv1 xenograft model. Conclusions: Small molecule inhibition of the bromodomain of p300/CBP, leads to down-regulation of AR, ARV and c-Myc as well as inhibition of key downstream PD biomarkers including PSA and TMPRSS2 and represents a promising new approach for the treatment of CRPC.

scholarly journals NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy

2019 ◽  
Vol 8 (4) ◽  
pp. 442 ◽  
Author(s):  
Toshiki Etani ◽  
Taku Naiki ◽  
Aya Naiki-Ito ◽  
Takayoshi Suzuki ◽  
Keitaro Iida ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Neuroendocrine Differentiation ◽  
Cancer Growth ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.

Molecular and genomic characterization of invasive circulating tumor cells (iCTCs) from men with metastatic castration-resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 120-120
Author(s):  
Terence W. Friedlander ◽  
Gayatri Premasekharan ◽  
Vy Ngo ◽  
Shaun Doty ◽  
Anna Harris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Ex Vivo ◽  
Genomic Analysis ◽  
Comparative Genomic ◽  
Castration Resistant Prostate Cancer ◽  
Culture Methods ◽  
Castration Resistant

120 Background: Identification, enumeration, and genomic analysis of circulating tumor cells (CTCs) may allow for a better understanding of the mechanisms of resistance to therapies in metastatic castration-resistant prostate cancer (mCRPC). The Vitatex VitaAssay platform captures invasive CTCs (iCTCs) in a cell surface marker-independent fashion based on their ability to invade a fluorescently-labeled cell-adhesion matrix (CAM), allowing for the analysis of multiple CTC subpopulations. Here we sought to estimate epithelial, mesenchymal, and stem-like iCTC subpopulation diversity in men with CRPC starting abiraterone acetate therapy, to compare the genomic profiles of iCTCs to matched metastatic biopsies, and to explore the potential for 2D and 3D CTC culture. Methods: iCTCs were isolated from men with mCRPC using the CAM platform, and paired metastatic biopsies were performed. iCTCs were defined as CAM+/CD45-/CD14-/DAPI+, mesenchymal iCTCs as vimentin+/CAM+/CD45-/CD14-/DAPI+, and stem-like iCTCs as CD44+/CAM+/CD45-/CD14-/DAPI+. iCTCs were enumerated and purified using FACS. Agilent array comparative genomic hybridization (aCGH) of iCTCs and paired biopsies was performed, and to explore the potential for ex-vivo cell expansion and spheroid formation, iCTCs were cultured separately in CAM and in matrigel for up to 10 days. Results: iCTCs were isolated using the CAM platform from 29 men, of whom seven have undergone paired metastatic biopsy. The median pre-FACS purity was 1.06% (range 0.11%-10.16%). Post-FACS purity was increased to greater than 90%, and a median of 60 (range 2 to 1,314) iCTCs/7.5ml were detected by FACS. Both vimentin+ and CD44+ iCTCs are detectable, and compromise between 10 to 50% of total iCTCs. iCTC aCGH profiles resemble paired soft tissue biopsy, in vitro iCTCs culture is feasible, and iCTC spheroids were observed. Conclusions: Multiple CRPC iCTC subpopulations are identifiable from men starting abiraterone therapy, and cell sorting techniques increase iCTC purity. iCTCs resemble metastatic CRPC tissue and can be expanded in culture. Further enumeration, genomic profiling, and clinical correlation of paired iCTCs taken from men with abiraterone-resistant CRPC is underway, and may shed light on mechanisms of abiraterone resistance.

scholarly journals Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer

2021 ◽  
Vol 118 (40) ◽  
pp. e2103623118
Author(s):  
Thomas Bello ◽  
Claudia Paindelli ◽  
Luis A. Diaz-Gomez ◽  
Anthony Melchiorri ◽  
Antonios G. Mikos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Computational Modeling ◽  
Late Stage ◽  
Kinase Inhibitors ◽  
Ex Vivo ◽  
Growth Factor Signaling ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.

scholarly journals YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Hsiu-Chi Lee ◽  
Chien-Hui Ou ◽  
Yun-Chen Huang ◽  
Pei-Chi Hou ◽  
Chad J. Creighton ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lipid Metabolism ◽  
Critical Issue ◽  
Castration Resistant Prostate Cancer ◽  
Cancer Stemness ◽  
New Treatment ◽  
Underlying Mechanisms ◽  
Transcriptional Complex

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

scholarly journals PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2731
Author(s):  
Piotr Garnuszek ◽  
Urszula Karczmarczyk ◽  
Michał Maurin ◽  
Arkadiusz Sikora ◽  
Jolanta Zaborniak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Ex Vivo ◽  
Specific Binding ◽  
Biological Evaluation ◽  
In Vitro Assays ◽  
The Novel ◽  
Distribution Profile ◽  
System L

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity >97%. The radio complexes were obtained with high yields (>97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol−1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases.

scholarly journals In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

2021 ◽  
Vol 7 (27) ◽  
pp. eabg2564
Author(s):  
Nathalie Bock ◽  
Thomas Kryza ◽  
Ali Shokoohmand ◽  
Joan Röhl ◽  
Akhilandeshwari Ravichandran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Adaptive Responses ◽  
Metastatic Tissue ◽  
Metastatic Lesions ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

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