Three papers describe promising new ways in which the androgen receptor (AR) might be targeted to overcome resistance to anti-androgen therapy for prostate cancer.
Anti-androgens, such as bicalutamide, are used to treat advanced prostate cancer, but eventually the tumours become androgen independent (known as castration-resistant prostate cancer, CRPC). Three recent papers have identified promising new ways in which the androgen receptor (AR) might be targeted to overcome resistance.
Neil Smith
A cause of anti-androgen resistance is increased expression of AR, a transcription factor, so Tran et al. investigated whether compounds that maintain AR antagonism in the presence of high AR expression might be valid second-generation anti-androgens. They identified two lead compounds, RD162 and MDV3100, which had a greater affinity for AR than bicalutamide. In LNCaP human prostate cancer cells, both agents reduced AR nuclear translocation and DNA binding. RD162 and MDV3100 induced significant tumour regression in CRPC mouse xenograft models using LNCaP or LAPC4 prostate cancer cells. MDV3100 is being tested in a Phase I and II clinical trial in 30 men with CRPC who have progressed on first-line anti-androgens. Preliminary data have shown that prostate-specific antigen (PSA) levels were reduced by 50% in 13 patients, and results from a larger trial will be reported separately.
Xu et al. conducted a screen for proteins that bind AR and identified the E3 ubiquitin ligase RING finger protein 6 (RNF6). Although RNF6 induced polyubiquitylation of AR, it did not promote AR degradation. Rather, it seems to promote AR transcriptional activity, as RNF6 knockdown by short hairpin RNA (shRNA) altered the recruitment of AR to some target genes and hence altered the gene expression profile in LNCaP cells. Ubiquitylation may affect AR transcriptional activity by influencing the recruitment of transcription cofactors. Using human prostate tissue arrays, the authors also showed that RNF6 is highly expressed in CRPCs compared with benign or hormone-naive samples. RNF6 shRNA inhibited the growth of C4-2B and CWR-R1 human prostate cancer cells in vitro and when xenografted into castrated immunodeficient mice. These data suggest that RNF6 or other members of the ubiquitylation machinery could be valid therapeutic targets in prostate cancer.
Because available anti-androgens (such as bicalutamide) are competitive antagonists that target ligand binding, non-competitive inhibitors of AR might be useful therapeutically. Jones et al. identified two such antagonists: the US Food and Drug Administration-approved pyrvinium pamoate and the natural product harmol hydrochloride. These agents synergize with bicalutamide, as well as each other, to inhibit transcription of KLK 3 (which encodes PSA) in LNCaP cells, suggesting distinct mechanisms of action. Bicalutamide and harmol hydrochloride, but not pyrvinium pamoate, blocked AR binding to DNA in LNCaP cells; pyrvinium pamoate inhibited AR-dependent gene expression by blocking RNA polymerase II recruitment. Both agents also inhibited cell proliferation, although pyrvinium pamoate was more potent. Prostate atrophy, morphology and gene expression were used to evaluate anti-androgen activity in mice. Pyrvinium pamoate induced morphological signs of androgen deprivation in the prostate, inhibited AR-dependent gene expression and, in combination with bicalutamide, induced levels of atrophy similar to castration.
Although the data evaluating these targets or compounds are preliminary, they suggest promising strategies for combating CRPC.
Sarah Seton-Rogers
References
Jones, J. O. et al. Non-competitive androgen receptor inhibition in vitro and in vivo. Proc. Natl Acad. Sci. USA106, 7233–7238 (2009) | Article | PubMed |
Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science324, 787–790 (2009) | Article | PubMed |
Xu, K. et al. Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell15, 270–282 (2009) | Article | PubMed |
