A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones.
ABSTRACT To evaluate mifepristone (RU-486) in patients with castration-resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites
The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3 alpha-diol G, were measured at baseline and during therapy.
Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31-338) days. The median prostate-specific antigen (PSA) level at enrollment was 22.0 (3.0-937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline.
Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.
Article: "True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer.[show abstract] [hide abstract]
ABSTRACT: Prostate cancer (PCa) therapy typically involves administration of "classical" antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.Journal of Medicinal Chemistry 02/2012; 55(4):1635-44. · 4.80 Impact Factor