Purpose: The heterogeneity of androgen receptor (AR)activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatmentnaïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications.Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n ¼ 5,239) and validation (n ¼ 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n ¼ 1,170), and The Cancer Genome Atlas (n ¼ 333).Results: A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P ¼ 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P ¼ 0.008).Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
Purpose Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify agents those could target AR for both disease types. We provide mechanism-based evidence that Lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of AR in vitro and in vivo. Experimental Design Normal prostate epithelial cell (RWPE-1), LAPC4 (wild-functional AR/ADPC), LNCaP (mutant-functional/AR/ADPC) and C4-2b (mutant-functional/AR/CRPC) cells were used to test the anti-AR activity of Lupeol. Cells grown under androgen-rich environment and treated with Lupeol were tested for proliferation, AR-transcriptional activity, AR competitive ligand-binding, AR-DNA-binding and AR-ARE/target gene binding. Further, in silico molecular modeling for Lupeol-AR binding was performed. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intra-peritoneally with Lupeol (40 mg/kg; 3-times/week) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, Lupeol-serum levels were measured. Results Lupeol significantly inhibited R1881 (androgen-analogue)-induced (1) transcriptional activity of AR and (2) expression of PSA. Lupeol (1) competed antagonistically with androgen for AR, (2) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK and IL-6, and (3) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to anti-hormone therapy. HPLC analysis showed that Lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels. Conclusion Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.