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Therapeutic Implications for Castration-Resistant Prostate Cancer

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Therapeutic Implications for Castration-Resistant Prostate Cancer Research Article Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist after Testosterone Suppression: Therapeutic Implications for Castration-Resistant Prostate Cancer Elahe A. Mostaghel,1,2 Stephanie T. Page,2,5 Daniel W. Lin,3,5 Ladan Fazli,6 Ilsa M. Coleman,1 Lawrence D. True,4 Beatrice Knudsen,1 David L. Hess,7 Colleen C. Nelson,6 Alvin M. Matsumoto,2,5 William J. Bremner,2 Martin E. Gleave,6 and Peter S. Nelson1 1Fred Hutchinson Cancer Research Center; Departments of 2Medicine, 3Urology, and 4Pathology, University of Washington School of Medicine; 5Veterans Affairs Puget Sound Health Care System, Seattle, Washington; 6Vancouver General Hospital, Vancouver, British Columbia, Canada; and 7Oregon National Primate Research Center, Beaverton, Oregon Abstract efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contribu- Androgen deprivation therapy (ADT) remains the primary tions to the prostatic androgen microenvironment. treatment for advanced prostate cancer. The efficacy of ADT [Cancer has not been rigorously evaluated by demonstrating suppres- Res 2007;67(10):5033–41] sion of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of Introduction medical castration in suppressing prostatic androgen levels Androgens are important mediators of transcriptional pathways and androgen-regulated gene expression. Androgen levels and controlling the proliferation, differentiation, and apoptosis of androgen-regulated gene expression (by microarray profiling, normal and neoplastic prostate cells and play a critical role in the quantitative reverse transcription-PCR, and immunohisto- development and progression of prostate cancer. Androgen chemistry) were measured in prostate samples from a clinical deprivation therapy (ADT) is considered standard systemic trial of short-term castration (1 month) using the gonadotro- treatment for advanced prostate cancer, and is being increasingly pin-releasing hormone antagonist, Acyline, versus placebo in used in neoadjuvant and adjuvant protocols for the treatment of healthy men. To assess the effects of long-term ADT, gene high-risk, early-stage disease. Remarkably, the efficacy of ADT has expression measurements were evaluated at baseline and after not been rigorously evaluated in vivo by demonstrating effective 3, 6, and 9 months of neoadjuvant ADT in prostatectomy suppression at the target tissue and molecular level, either by samples from men with localized prostate cancer. Medical establishing complete ablation of tissue androgen levels or castration reduced tissue androgens by 75% and reduced the abrogation of androgen-mediated gene expression. Furthermore, expression of several androgen-regulated genes (NDRG1, heterogeneity in the clinical response to initial ADT and FKBP5, and TMPRSS2). However, many androgen-responsive secondary hormonal manipulations suggests that patient- and/ genes, including the androgen receptor (AR) and prostate- or tumor-specific factors modulate the degree of androgen specific antigen (PSA), were not suppressed after short-term deprivation achieved within the tumor and surrounding micro- castration or after 9 months of neoadjuvant ADT. Significant environment. heterogeneity in PSA and AR protein expression was observed Although the adequacy of ADT is routinely assessed based on in prostate cancer samples at each time point of ADT. Medical achieving castrate levels of serum testosterone, accumulating castration based on serum testosterone levels cannot be evidence suggests that despite medical castration, residual equated with androgen ablation in the prostate microenvi- androgens are present within the prostate at levels capable of ronment. Standard androgen deprivation does not consis- activating the androgen receptor (AR) and supporting continued tently suppress androgen-dependent gene expression. expression of androgen-dependent genes (1–5). A study of patients Suboptimal suppression of tumoral androgen activity may with benign prostatic hypertrophy (BPH) found that prostatic lead to adaptive cellular changes allowing prostate cancer cell testosterone and dihydrotestosterone levels were decreased by only survival in a low androgen environment. Optimal clinical 75% to 80% after achieving castrate serum testosterone levels with gonadotropin-releasing hormone agonist therapy (2). More recent- ly, Mohler et al. (3) reported that medically or surgically castrate patients with recurrent prostate cancer actually had prostatic Note: Supplementary data for this article are available at Cancer Research Online testosterone levels equivalent to those of patients with BPH, (http://cancerres.aacrjournals.org/). E.A. Mostaghel and S.T. Page contributed equally to the preparation of the whereas intraprostatic dihydrotestosterone levels were only manuscript. reduced by f75%. Importantly, in vitro and in vivo studies have Disclosure statement: E.A. Mostaghel, S.T. Page, D.W. Lin, L. Fazli, I.M. Coleman, shown that dihydrotestosterone levels in the range observed in the L.D. True, B. Knudsen, D.L. Hess, and C.C. Nelson have nothing to disclose. A.M. Matsumoto, W.J. Bremner, M.E. Gleave, and P.S. Nelson have consulted for prostatic tissue of castrated patients (0.5–1.0 ng/g) are sufficient to GlaxoSmithKline. P.S. Nelson and A.M. Matsumoto have consulted for Solvay activate the AR and stimulate expression of androgen-regulated Pharmaceuticals. A.M. Matsumoto has received grant support from GlaxoSmithKline, Ascend Therapeutics, and Solvay Pharmaceuticals. genes (3, 6–9). Requests for reprints: Peter S. Nelson, Fred Hutchinson Cancer Research Center, To date, human studies examining the association between 1100 Fairview Avenue North, MS D4-100, Seattle, WA 91809. Phone: 206-667-3506; prostate gene expression and tissue androgen levels have been Fax: 206-667-2917; E-mail: [email protected]. I2007 American Association for Cancer Research. limited; most have relied on serum testosterone measurements in doi:10.1158/0008-5472.CAN-06-3332 the setting of castration as a surrogate for prostatic androgen www.aacrjournals.org 5033 Cancer Res 2007; 67: (10). May 15, 2007 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2007 American Association for Cancer Research. Cancer Research levels, an assumption now known to be inaccurate. We hypothe- for RNA analyses, as well as formalin fixed and paraffin embedded for sized that despite castrate levels of serum testosterone, the degree immunohistochemical analyses. Prostate tissue from a randomly selected n and uniformity of androgen deprivation in the tumor microenvi- subset of patients at each time point ( = 3 per group, at 0, 3–6, and 6–9 ronment may be inadequate to consistently ablate androgen months of treatment) were used to assess gene and protein expression. activity, as assessed by androgen-dependent gene expression. In PSA and Hormone Measurements this setting, incomplete suppression of tumoral androgen activity Serum PSA was measured in the Department of Laboratory Medicine, may lead to adaptive cellular changes, allowing tumor survival and University of Washington, using a Hybritech Enzyme Immunoassay with proliferation in a low androgen environment. This scenario could inter- and intra-assay coefficient of variations of 2% to 4%. Serum and explain the near-universal emergence of castration-resistant prostate testosterone and dihydrotestosterone levels were measured in the disease and offers an alternative to theories that postulate the Endocrine Services Laboratory of the Oregon National Primate Research existence of rare androgen-independent neoplastic clones early in Center as previously described (5, 13). In brief, samples were extracted with diethyl ether and fractionated by liquid chromatography using hexane/ tumorigenesis, or a requirement for genetic mutations producing benzene/methanol, with assay of testosterone and dihydrotestosterone selective growth advantages. concentrations in the appropriate fractions by RIA (14). To determine the effect of medical castration on the intra- prostatic androgen milieu, we evaluated the effects of both short- Histology and Immunohistochemistry term and prolonged androgen suppression on prostatic androgen- Immunohistochemical staining and image analysis of frozen tissue responsive gene and protein expression. We did a randomized sections from the Acyline trial for PSA (polyclonal anti-PSA, DAKO, Inc.) clinical trial of short-term castration in healthy men and obtained and AR (monoclonal anti-AR, clone F36.4.1, BioGenex) was done as recently described (5). In brief, 5-Am frozen tissue sections were stained using an prostate core biopsies to measure tissue androgen levels and avidin-biotin-peroxidase complex as the tertiary reagent (Vector Labs) and epithelial cell gene expression. To determine the efficacy and diaminobenzidine (DAB) as the chromogen. Images were made at Â40 and uniformity of standard ADT in ablating androgen-dependent gene digitized with a SPOT Insight camera (model 3.2.0, Diagnostics Instruments, expression in neoplastic tissue, we also evaluated the suppression Inc.), using the same light intensity and color thresholding for all sections of of androgen-regulated gene and protein expression in primary each stain. Image analysis was done using Image Pro-Plus version 4.2 prostate cancer specimens from men with localized prostate software (Media Cybernetics, Inc.). The percentage of total epithelial area cancer treated with
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