Characterization of an abiraterone ultra-responsive phenotype in castration-resistant prostate cancer patient-derived xenografts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85672 | GEO | 2016/12/22
SECONDARY ACCESSION(S): PRJNA339045
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of the patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.
2018-03-20 | GSE108462 | GEO
Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.
2018-12-13 | GSE123695 | GEO
Project description:We report RNA sequencing data on serial biopsies of prostate cancer VCaP xenografts as the tumors pass from androgen-sensitivity (Pre-Cx), to castration resistance (CRPC, castration resistant prostate cancer), onto resistance to dual therapy with abiraterone plus enzalutamide (AER). From comparison of these RNAseq data sets, we were able to determine differentially expressed genes between the AER/CRPC and Pre-Cx states that could mediate resistance to androgen deprivation therapies.
2018-12-26 | GSE109708 | GEO
Project description:The goal of this study was to determine the effects of a well-characterized anti-androgen, abiraterone acetate, and a suspected human anti-androgen, di-n-butyl phthalate (DBP) on the androgenic function of human fetal testis. Human fetal testis was xenografted into the renal subcapsular space of castrated male athymic nude mice. Hosts were treated with hCG to stimulate testosterone production in the xenografts, and were concurrently treated with either abiraterone acetate or DBP. While abiraterone acetate (14 d, 75 mg/kg/d p.o.) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500 mg/kg/d p.o.) had no effect on androgenic endpoints. Three paired analyses were performed using the LIMMA package in R (commands lmfit and eBayes), with the Benjamini-Hochberg correction for multiple comparisons (Smyth 2005): vehicle-treated xenografts vs. unimplanted testis (n=5), abiraterone-treated xenografts vs. matched control xenografts (n=3), and DBP-treated xenografts vs. matched control xenografts (n=3). There were significant differences in gene expression between grafted and ungrafted samples, including dramatic upregulation of microRNAs. Gene expression analysis also showed that abiraterone decreased expression of genes related to cell differentiation, while DBP induced expression of oxidative stress response genes and decreased expression of factors related to embryonic development. 17 xenograft samples were analyzed, including 5 unimplanted samples, 6 vehicle treated xenografts, 3 abiraterone acetate-treated xenografts, and 3 DBP-treated xenografts. Samples were paired (derived from the same donor tissue) for each comparison: vehicle vs. unimplanted (n=5), abiraterone vs. vehicle (n=3), and DBP vs. vehicle (n=3).
2013-10-31 | E-GEOD-49244 | biostudies-arrayexpress
Project description:Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC)
| PRJNA509610 | ENA
Project description:Castration resistant prostate cancer (CRPC) develops resistance to antiandrogens affecting Androgen Receptor (AR) signaling through a variety of mechanism. Because of this, the efficacy of androgen receptor targeted therapy remains limited for many patients with CRPC. We developed C42B-Abiraterone (Abi) and resistance cells to study changes in transcriptomic profile compared to parental cells.
2023-01-01 | GSE220467 | GEO
Project description:The goal of this study was to determine the effects of a well-characterized anti-androgen, abiraterone acetate, and a suspected human anti-androgen, di-n-butyl phthalate (DBP) on the androgenic function of human fetal testis. Human fetal testis was xenografted into the renal subcapsular space of castrated male athymic nude mice. Hosts were treated with hCG to stimulate testosterone production in the xenografts, and were concurrently treated with either abiraterone acetate or DBP. While abiraterone acetate (14 d, 75 mg/kg/d p.o.) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500 mg/kg/d p.o.) had no effect on androgenic endpoints. Three paired analyses were performed using the LIMMA package in R (commands lmfit and eBayes), with the Benjamini-Hochberg correction for multiple comparisons (Smyth 2005): vehicle-treated xenografts vs. unimplanted testis (n=5), abiraterone-treated xenografts vs. matched control xenografts (n=3), and DBP-treated xenografts vs. matched control xenografts (n=3). There were significant differences in gene expression between grafted and ungrafted samples, including dramatic upregulation of microRNAs. Gene expression analysis also showed that abiraterone decreased expression of genes related to cell differentiation, while DBP induced expression of oxidative stress response genes and decreased expression of factors related to embryonic development.
2013-10-31 | GSE49244 | GEO
Project description:Background: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients' life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. Objective: To identify predictive serum biomarkers for Abi treatment. Design, setting, and participants: We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection methods were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Outcome measurements and statistical analysis: Serum levels were correlated with patients‘ clinicopathological parameters and survival. Results and limitations: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering methods four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p<0.001 and p=0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. Conclusions: Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1. Patient summary: In this study, we identified serum FSCN1 as a marker that may help to predict PCa patients who derive less benefit from Abi but not Doc treatment.
2023-08-28 | PXD038697 | Pride
Project description:Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients
| PRJNA427328 | ENA
Project description:We reported the tumor total gene expression TRAF4-overexpressing castration-resistant xenograft tumors and the control castration-responsive tumors
2020-07-15 | GSE154029 | GEO