Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist after Testosterone Suppression: Therapeutic Implications for Castration-Resistant Prostate Cancer

Abstract

Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostatespecific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment. [Cancer Res 2007;67(10):5033-41]

Early and delayed castrations confer a similar survival advantage in TRAMP mice

“…However, standard androgen deprivation did not consistently suppress androgen-dependent gene expression. Many androgen-responsive genes were not suppressed even after 9 months of neoadjuvant androgen deprivation therapy [30]. Androgenindependent prostate cancer may be the consequence of molecular events that are mediated by abnormal androgen receptor signalling.…”

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…ADT with either surgical or medical castration usually results in a response rate of 70-80% with a 12-33 months duration of progression-free survival . However, after an average of 24 months, the tumors almost always recur and no longer respond to ADT (Eisenberger et al, 1998), even though the prostate tumors still express AR Mostaghel et al, 2007). Interestingly, cell sorting of these ADT-refractory tumors found that the prostatic epithelial basal cell marker, cytokeratin 5 (CK5) (Bruchovsky et al, 1990;van Leender et al, 2001) increased from 29 to 75%, an observation consistent with the expansion of basal intermediate-like tumor cells observed in transgenic adenocarcinoma mouse prostate (TRAMP) mice with selective knockout of AR (ARKO) in prostatic epithelium (pes-ARKO-TRAMP) and inducible ARKO-TRAMP (ind-ARKO-TRAMP) mice (see details in section 'AR dual functions in prostate cancer progression and metastasis').…”

Extracellular influences on tumour angiogenesis in the aged host

“…However, there is invariably a return of tumour that is castration resistant. These tumours are commonly referred to as androgen-independent (AI), although castration-resistant may be a more appropriate term since they still contain significant levels of T and dihydrotestosterone (Mostaghel et al, 2007). In castration-resistant tumours, there is an increase in angiogenesis that is associated with an increase in MMP-9 (London et al, 2003).…”