Androgen receptor degradation (ARD) enhancers: a targeted therapy for hormone-refractory prostate cancer

Proc Amer Assoc Cancer Res, Volume 47, 2006 4710 Prostate cancer is the second leading cancer death for men in the United States. The androgen receptor (AR) plays a critical role in the development of prostate cancer. Total androgen blockade through a combination of castration and antiandrogens is a conventional treatment for primary prostate cancer. However, the tumors almost always relapse and become hormone-refractory. AR continues to express and appears to overly express in many relapsed tumors. Residual androgenic activity of antiandrogens or the so-called “nonconventional AR ligands” have been attributed to the occurrence of hormone-refractory tumors. In this report, we demonstrated that a new group of compounds, ASCJ, inhibits AR functional activity through a novel mechanism, i.e., enhancing AR degradation, and may have potential for treating hormone-refractory prostate cancer. ASCJ compounds, derivatives of a natural compound, at concentrations ranging from 0.5 to 2.5 μM decreased AR protein expression in human prostate cancer LNCaP and CWR22 cell lines; a cycloheximide chase study showed that under the experimental conditions, ASCJ compounds enhanced AR degradation. Data derived from a mammalian two-hybrid protein assay illustrated that ASCJ compounds, unlike the classic antiandrogens (cyproterone acetate and hydroxyflutamide), did not interfere with AR dimerization and AR-coactivator (ARA70) interaction in the presence of androgens, indicating that ASCJ compounds possess an anti-AR mechanism significantly different from the conventional antiandrogens. At cellular level, ASCJ compounds alone at various concentrations were unable to stimulate AR transactivation, indicating an absence of “residual androgenic” activity in this new class of compounds. But at pharmacologically achievable concentrations, ASCJ compounds markedly inhibited androgen-induced transactivation of both wild type and mutant ARs (in LNCaP and CWR22 cells). ASCJ compounds also suppressed AR transcriptional activity induced by the “nonconventional AR ligands”, including estradiol and adrenal androgens (androstenediol or dehydroepiandrosterone), as well as classic antiandrogens (cyproterone acetate and hydroxyflutamide). In an LNCaP xenograft animal model, intraperitoneal injection of a lead ASCJ compound (at 100 mg/kg body weight, three times per week) significantly hindered prostate tumor growth. In conclusion, these data demonstrate that ASCJ compounds, which enhance AR degradation, are powerful AR functional inhibitors both in vitro and in vivo . Since most relapsed prostate cancers are AR-dependent and in many cases overly express AR, the ARD Enhancers such as ASCJ compounds, may be ideal drug candidate to be developed into a target-specific therapy for hormone-refractory prostate cancer.