Beyond Castration—Defining Future Directions in the Hormonal Treatment of Prostate Cancer

Abstract

It is now almost 70 years since Charles Huggins described the relationship between testosterone and the prostate gland. Arguably defining one of the first targeted therapies, the reduction of testosterone to castrate levels remains unaltered as the standard of care for men with metastatic prostate cancer. The failure of castration to permanently control the growth of prostate cancer leads to a state called castration-resistant prostate cancer (CRPC).

TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

“…On a molecular level, the steroid hormone androgen activates the androgen receptor (AR), which in turn functions as a nuclear receptor transcription factor and executes specific tumorigenic gene expression programs (Matsumoto et al, 2013; Wang et al, 2009). Therefore, advanced cancer therapy includes androgen-deprivation approaches through inhibition of androgen synthesis and the administration of competitive AR antagonists (Niraula et al, 2012). Unfortunately, most patients develop resistance to treatment and subsequently progress to castration-resistant disease (CRPC) that in most cases continues to rely on AR signaling (Heinlein and Chang, 2004; Scher and Sawyers, 2005).…”

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

“…Inversely, androgen deprivation therapy, which reduces androgen production, or antiandrogen agents, which interfere with AR function, are gold-standard treatments for recurrent or advanced prostate cancer (Miyamoto et al 2004). However, androgen-dependent prostate cancer eventually develops into castration-resistant prostate cancer (CRPC), which can be attributable to augmented prosurvival and anti-apoptotic properties by AR signaling and others (Niraula et al 2012). Against CRPC, few therapeutics including taxane chemotherapy are not curative, only ameliorating cancer-caused symptoms and prolonging survival for a few months.…”

The androgen receptor for the radiation oncologist

“…Clinical trials are ongoing. Galeterone (TOK-001) inhibits CYP17 at low concentration, but at higher doses, it could inhibit the androgen receptor and even facilitates its degradation [60].…”