BERKELEY, CA (UroToday.com) - Men with advanced castration-resistant prostate cancer (CRPC) die of their disease due to failure of mainstay anti-androgen treatment that should suppress prostate tumor growth. While novel and more potent inhibitors of androgen receptor signaling, such as the recently approved enzalutamide, do increase survival, this advantage is only a matter of months. Thus, resistance to second-generation anti-androgens is the most critical unmet medical need for men with CRPC.
Since the time of Huggins and Hodges, androgen deprivation of prostate tumors has been the most consistently used form of therapy for both early- and late-stage prostate cancer. Indeed, when used in combination with prostatectomy or radiotherapy, androgen depravation therapy (ADT) improves overall and cancer-specific survival, and it is useful in palliation.[1] Thus, even in the era where patients receiving enzalutamide progress with rising PSA, indicating that AR activity is suppressed for only a short period of time, the ligand-binding domain of the AR continues to be a favored therapeutic target. Indeed, in the recent study by Kuruma et al.,[2] the authors clearly show that the novel third-generation anti-androgen, Cpd30, suppresses AR expression, transcriptional activity, and nuclear translocation better than enzalutamide in androgen-dependent and CRPC prostate cancer cell lines. Moreover, this drug was as effective as enzalutamide at suppressing cell line growth in vitro and in xenograft models. The authors suggest that the increased efficacy of Cpd30 over enzalutamide may be its ability to modulate not only nuclear accumulation of AR, but also its expression, via downregulation of the AR- binding transcription factor YB-1 (Kuruma et al., data not shown).[2] Overall, these data suggest that new anti-androgens targeting the ligand-binding domain of AR may have novel mechanisms of AR suppression and may provide survival advantages in patients with CRPC, over enzalutamide, or when used sequentially, or in combination with this treatment.
More important than identifying another anti-androgen that can target CRPC, Kuruma et al. show efficacy of Cpd 30 against enzalutamide-resistant CRPC cells -- both in vitro and in vivo. As in patients treated with enzalutamide, the authors observed recurrence and increased PSA in LNCaP CRPC xenografts treated with enzalutamide. These resistant tumors were transplanted into castrated, enzalutamide-treated mice and upon recurrence were serially transplanted under constant enzalutamide treatment. After three generations, enzalutamide-resistant cells were established in vitro and used to model the efficacy of Cpd 30 in the post-enzalutamide setting. Strikingly, Cpd30, but not enzalutamide, was able to suppress AR expression, nuclear translocation and activity, as well as proliferation in these resistant cells. In addition, Cpd 30 suppressed the growth of enzalutamide-resistant xenografts in vivo, suggesting its utility in enzalutamide-resistant patients to further prolong survival.
Despite these encouraging results, the authors also highlight that enzalutamide-resistant tumors treated with Cpd30 eventually recurred, underscoring the continued failure of therapies targeting classical AR signaling to prevent progression of CRPC. Although studies such as these suggest that sequential therapy using anti-androgens like Cpd30 in enzalutamide-resistant patients, or combinatorial therapy using enzalutamide with Cpd30, may provide survival advantages, they also highlight that similar mechanisms of resistance gained in prostate tumors at an early stage of androgen deprivation impede the use of third-line therapies. Alternatively, novel mechanisms of resistance may be rapidly selected for in tumors that are exposed to the constant changing pressures of novel therapies. Interestingly, other unpublished data from the Zoubedi group suggests that changes in oncogenic signaling pathways, such as hyperactivation of ERK and AKT, also contribute to enzalutamide resistance. Therefore, one could speculate that a multi-armed combinatorial approach targeting classical AR activity with ligand binding domain inhibitors along with AKT or ERK inhibitors may be a more effective means of tumor control than targeting the AR alone.
References:
- Kirkbridge, R., et al., 2013. Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-effectiveness. British Journal of Cancer, 108(1), 9-13.
- Kuruma, H., et al., 2013. A Novel Antiandrogen, Compound 30, Suppresses Castration-Resistant and MDV3100-Resistant Prostate Cancer Growth In Vitro and In Vivo. Molecular Cancer Therapeutics, 12, 567-576.
Written by:
Jennifer L. Bishop, PhD and Amina Zoubeidi, BSc, M.Sc, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
The Vancouver Prostate Centre, Department of Urologic Science University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada
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