Dataset Information

Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer.

ABSTRACT: Androgen deprivation (AD) therapy failure leads to terminal and incurable castration-resistant prostate cancer (CRPC). We show that the redox-protective protein thioredoxin-1 (TRX1) increases with prostate cancer progression and in androgen-deprived CRPC cells, suggesting that CRPC possesses an enhanced dependency on TRX1. TRX1 inhibition via shRNA or a phase I-approved inhibitor, PX-12 (untested in prostate cancer), impedes the growth of CRPC cells to a greater extent than their androgen-dependent counterparts. TRX1 inhibition elevates reactive oxygen species (ROS), p53 levels and cell death in androgen-deprived CRPC cells. Unexpectedly, TRX1 inhibition also elevates androgen receptor (AR) levels under AD, and AR depletion mitigates both TRX1 inhibition-mediated ROS production and cell death, suggesting that AD-resistant AR expression in CRPC induces redox vulnerability. In vivo TRX1 inhibition via shRNA or PX-12 reverses the castration-resistant phenotype of CRPC cells, significantly inhibiting tumor formation under systemic AD. Thus, TRX1 is an actionable CRPC therapeutic target through its protection against AR-induced redox stress.

SUBMITTER: Samaranayake GJ

PROVIDER: S-EPMC5663934 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer.

Samaranayake Govindi J GJ Troccoli Clara I CI Huynh Mai M Lyles Rolando D Z RDZ Kage Karen K Win Andrew A Lakshmanan Vishalakshi V Kwon Deukwoo D Ban Yuguang Y Chen Steven Xi SX Zarco Enrique Rodriguez ER Jorda Merce M Burnstein Kerry L KL Rai Priyamvada P

Nature communications 20171031 1

Androgen deprivation (AD) therapy failure leads to terminal and incurable castration-resistant prostate cancer (CRPC). We show that the redox-protective protein thioredoxin-1 (TRX1) increases with prostate cancer progression and in androgen-deprived CRPC cells, suggesting that CRPC possesses an enhanced dependency on TRX1. TRX1 inhibition via shRNA or a phase I-approved inhibitor, PX-12 (untested in prostate cancer), impedes the growth of CRPC cells to a greater extent than their androgen-depend ...[more]

PMID: 29089489

Similar Datasets

Project description:ImportanceNovel androgen receptor inhibitors (ARIs; darolutamide, enzalutamide, and apalutamide) are standard-of-care treatments for nonmetastatic castration-resistant prostate cancer (nmCRPC). However, there are sparse data comparing their clinical use and tolerability.ObjectiveTo compare clinical use and outcomes for darolutamide, enzalutamide, and apalutamide in patients with nmCRPC.Design, setting, and participantsThis retrospective cohort study reviewed electronic medical records from the Precision Point Specialty network of US urology practices. Eligible patients had nmCRPC and no prior novel hormonal therapy and initiated novel ARI treatment between August 1, 2019, and March 31, 2022. Data were analyzed from February 1, 2019, to December 31, 2022.ExposuresPatients were prescribed darolutamide, enzalutamide, or apalutamide as their first novel ARI for nmCRPC.Main outcomes and measuresThe main outcome was a composite of 2 end points, treatment discontinuation and progression to metastatic CRPC (mCRPC), whichever occurred first. Both end points were also assessed separately.ResultsAll 870 patients meeting eligibility criteria were included (362 receiving darolutamide [41.6%]; 382, enzalutamide [43.9%]; 126, apalutamide [14.5%]); mean (SD) age was 78.8 (8.7) years. Self-reported race was Black or African American in 187 patients (21.5%), White in 585 (67.2%), and other or unknown in 98 (11.3%). The darolutamide cohort had lower proportions of patients with a composite end point event (134 [37.0%] vs 201 [52.6%] for enzalutamide and 66 [52.4%] for apalutamide), discontinuation (110 [30.4%] for darolutamide vs 156 [40.8%] for enzalutamide and 58 [46.0%] for apalutamide), and progression to mCRPC (64 [17.7%] for darolutamide vs 108 [28.3%] for enzalutamide and 35 [27.8%] for apalutamide) during the study period. After adjusting for baseline covariates, patients receiving darolutamide had a lower risk of a composite end point event compared with enzalutamide (risk reduction, 33.8%; hazard ratio [HR], 0.66 [95% CI, 0.53-0.84]) and apalutamide (risk reduction, 35.1%; HR, 0.65 [95% CI, 0.48-0.88]). Similarly, patients receiving darolutamide had a lower risk of discontinuation compared with enzalutamide (risk reduction, 27.4%; HR, 0.73 [95% CI, 0.56-0.94]) and apalutamide (risk reduction, 39.1%; HR, 0.61 [95% CI, 0.44-0.85]) and a lower risk of progression to mCRPC compared with enzalutamide (risk reduction, 40.6%; HR, 0.59 [95% CI, 0.43-0.82]) and apalutamide (risk reduction, 35.3%; HR, 0.65 [95% CI, 0.42-0.99]). There was no difference between enzalutamide and apalutamide treatment across outcomes.Conclusions and relevanceIn this large cohort study of patients with nmCRPC treated with novel ARIs, results suggest better tolerability for darolutamide compared with enzalutamide and apalutamide, which may be associated with a clinical effectiveness advantage. Comparative clinical studies are needed to guide treatment decisions in the absence of head-to-head clinical trials.

Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Dataset Information

Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer.

Publications

Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets