Dataset Information

Inhibition of androgen receptor and ?-catenin activity in prostate cancer.

ABSTRACT: Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear ?-catenin activity (called C3) can inhibit both the AR and ?-catenin-signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both ?-catenin/T-cell factor and ?-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on ?-catenin. Given that AR interacts with, and is transcriptionally regulated by ?-catenin, C3 treatment also resulted in decreased occupancy of ?-catenin on the AR promoter and diminished AR and AR/?-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and ?-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of ?-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.

SUBMITTER: Lee E

PROVIDER: S-EPMC3785716 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Inhibition of androgen receptor and β-catenin activity in prostate cancer.

Lee Eugine E Madar Aviv A David Gregory G Garabedian Michael J MJ Dasgupta Ramanuj R Logan Susan K SK

Proceedings of the National Academy of Sciences of the United States of America 20130909 39

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin-signaling pathways that are often misregulated in prostate ...[more]

PMID: 24019458

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Project description:Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies.

Dataset Information

Inhibition of androgen receptor and ?-catenin activity in prostate cancer.

Publications

Inhibition of androgen receptor and β-catenin activity in prostate cancer.

Similar Datasets

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