Dataset Information

Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.

ABSTRACT: A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy.

SUBMITTER: Qin J

PROVIDER: S-EPMC4347241 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.

Qin Jun J Lee Hui-Ju HJ Wu San-Pin SP Lin Shih-Chieh SC Lanz Rainer B RB Creighton Chad J CJ DeMayo Francesco J FJ Tsai Sophia Y SY Tsai Ming-Jer MJ

The Journal of clinical investigation 20141008 11

A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpresse ...[more]

PMID: 25295534

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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.

Project description:BACKGROUND:Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS. METHODS:Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors. RESULTS:Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1?ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8?ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI?=?1.01-1.03, p?=?0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ?50% decline in PSA with an odds ratio of 0.93 (95% CI?=?0.85-0.98, p-value?=?0.039). CONCLUSIONS:Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

Dataset Information

Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.

Publications

Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.

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