Urologic Oncology: Seminars and Original Investigations
Volume 27, Issue 3 , Pages 251-257 , May 2009

Castration-resistant prostate cancer: Targeting androgen metabolic pathways in recurrent disease

☆☆Presented as part of the SUO/SBUR 2007 Annual Meeting, Anaheim, CA, May 2007. Program Director: Christopher Evans, M.D.

Received 8 February 2009 ,Revised 10 March 2009 ,Accepted 10 March 2009.

References 

  1. Huggins C, Hodges CV. Studies on prostate cancer. 1: The effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297
  2. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45
  3. Debes JD, Comuzzi B, Schmidt LJ, et al. p300 Regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res. 2005;65:5965–5973
  4. Gao H, Ouyang X, Banach-Petrosky WA, et al. Emergence of androgen independence at early stages of prostate cancer progression in nkx3.1; PTEN mice. Cancer Res. 2006;66:7929–7933
  5. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–39(Epub 2003 Dec. 21)
  6. Geller J, Liu J, Albert J, et al. Relationship between human prostatic epithelial cell protein synthesis and tissue dihydrotestosterone level. Clin Endocrinol (Oxf). 1987;26:155–161
  7. Liu J, Albert J, Geller J. Effects of androgen blockade with ketoconazole and megestrol acetate on human prostatic protein patterns. Prostate. 1986;9:199–205
  8. Liu J, Geller J, Albert J, et al. Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue. J Clin Endocrinol Metab. 1985;61:129–133
  9. Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: A marked improvement in response and survival. J Steroid Biochem. 1985;23:833–841
  10. Geller J, Albert J, Nachtsheim D, et al. Steroid levels in cancer of the prostate—markers of tumor differentiation and adequacy of anti-androgen therapy. Prog Clin Biol Res. 1979;33:103–111
  11. Geller J, Albert J, Vik A. Advantages of total androgen blockade in the treatment of advanced prostate cancer. Semin Oncol. 1988;15:53–61
  12. Geller J. Review of assessment of total androgen blockade as treatment of metastatic prostate cancer. J Endocrinol Invest. 1991;14:881–891
  13. Mohler JL, Gregory CW, Ford OH, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440–448
  14. Nishiyama T, Hashimoto Y, Takahashi K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin Cancer Res. 2004;10:7121–7126
  15. Nishiyama T, Ikarashi T, Hashimoto Y, et al. The change in the dihydrotestosterone level in the prostate before and after androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. J Urol. 2007;178:1282–1289
  16. Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033–5041
  17. Page ST, Lin DW, Mostaghel EA, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006;91:3850–3856
  18. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–2825
  19. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–4454
  20. Gregory CW, Johnson RT, Mohler JL, et al. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892–2898
  21. Culig Z, Hoffmann J, Erdel M, et al. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer. 1999;81:242–251
  22. Scher HI, Buchanan G, Gerald W, et al. Targeting the androgen receptor: Improving outcomes for castration-resistant prostate cancer. Endocrinol Relat Cancer. 2004;11:459–476
  23. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–8261
  24. Labrie F, Dupont A, Belanger A, et al. New hormonal therapy in prostatic carcinoma: Combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med. 1982;5:267–275
  25. Caubet JF, Tosteson TD, Dong EW, et al. Maximum androgen blockade in advanced prostate cancer: A meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens. Urology. 1997;49:71–78
  26. Schmitt B, Bennett C, Seidenfeld J, et al. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev. 2000;CD001526
  27. Singh SM, Gauthier S, Labrie F. Androgen receptor antagonists (anti-androgens): Structure–activity relationships. Curr Med Chem. 2000;7:211–247
  28. Kolvenbag GJ, Furr BJ, Blackledge GR. Receptor affinity and potency of non-steroidal antiandrogens: Translation of preclinical findings into clinical activity. Prostate Cancer Prostatic Dis. 1998;1:307–314
  29. Greenberg E. Endocrine therapy in the management of prostatic cancer. Clin Endocrinol Metab. 1980;9:369–381
  30. Robinson MR, Shearer RJ, Fergusson JD. Adrenal suppression in the treatment of carcinoma of the prostate. Br J Urol. 1974;46:555–559
  31. Harris KA, Weinberg V, Bok RA, et al. Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol. 2002;168:542–545
  32. Shearer RJ, Hendry WF, Sommerville IF, et al. Plasma testosterone: An accurate monitor of hormone treatment in prostatic cancer. Br J Urol. 1973;45:668–677
  33. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025–1033
  34. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164:217–227
  35. Labrie F. Adrenal androgens and intracrinology. Semin Reprod Med. 2004;22:299–309
  36. Belanger B, Belanger A, Labrie F, et al. Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: Unique importance of extratesticular androgens in men. J Steroid Biochem. 1989;32:695–698
  37. Mizokami A, Koh E, Fujita H, et al. The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res. 2004;64:765–771
  38. Miyamoto H, Yeh S, Lardy H, et al. δ5-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci USA. 1998;95:11083–11088
  39. Koh E, Kanaya J, Namiki M. Adrenal steroids in human prostatic cancer cell lines. Arch Androl. 2001;46:117–125
  40. Harper ME, Pike A, Peeling WB, et al. Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol. 1974;60:117–125
  41. Montgomery B, Mostaghel E, Vessella R, et al. Androgen synthesis in castration-adapted metastatic prostate cancer. J Clin Oncol. 2007;25:98;(2007 ASCO Annual Meeting Proceedings).
  42. Koh E, Noda T, Kanaya J, et al. Differential expression of 17beta-hydroxysteroid dehydrogenase isozyme genes in prostate cancer and noncancer tissues. Prostate. 2002;53:154–159
  43. Ashida S, Nakagawa H, Katagiri T, et al. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: Genome-wide gene expression profiles of prostate cancers and PINs. Cancer Res. 2004;64:5963–5972
  44. Fung KM, Samara EN, Wong C, et al. Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17 β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocrinol Relat Cancer. 2006;13:169–180
  45. Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab. 2004;15:432–438
  46. Small EJ, Baron AD, Fippin L, et al. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol. 1997;157:1204–1207
  47. Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005;96:1241–1246
  48. Handratta VD, Vasaitis TS, Njar VC, et al. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: Synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005;48:2972–2984
  49. Ryan CJ. Phase I evaluation of abiraterone acetate (CB7630), a 17alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer (AiPC). J Clin Oncol. 2007;Part 1:5064;(2007 ASCO Annual Meeting Proceedings)
  50. Attard G. Phase I study of continuous oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in castration refractory prostate cancer (CRPC) patients (p) incorporating the evaluation of androgens and steroid metabolites in plasma and tumor. J Clin Oncol. 2007;Part 1:5063;(2007 ASCO Annual Meeting Proceedings)
  51. Berube M, Poirier D. Chemical synthesis and in vitro biological evaluation of a phosphorylated bisubstrate inhibitor of type 3 17β-hydroxysteroid dehydrogenase. J Enzyme Inhib Med Chem. 2007;22:201–211
  52. Spires TE, Fink BE, Kick EK, et al. Identification of novel functional inhibitors of 17β-hydroxysteroid dehydrogenase type III (17β-HSD3). Prostate. 2005;65:159–170
  53. Stanway SJ, Purohit A, Woo LW, et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: The first study of a steroid sulfatase inhibitor. Clin Cancer Res. 2006;12:1585–1592
  54. Klein H, Molwitz T, Bartsch W. Steroid sulfate sulfatase in human benign prostatic hyperplasia: Characterization and quantification of the enzyme in epithelium and stroma. J Steroid Biochem. 1989;33:195–200
  55. Nakamura Y, Suzuki T, Fukuda T, et al. Steroid sulfatase and estrogen sulfotransferase in human prostate cancer. Prostate. 2006;66:1005–1012
  56. Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer. 2002;95:361–376

 This work was supported by a Career Development Award from the Prostate Cancer Foundation, a Damon Runyon-Genentech Clinical Investigator Award, and NIH grant 5K23 CA122820-02 (all to E.A.M.); and the NIH/NCI Pacific Northwest Prostate Cancer SPORE grant P50CA97186 (to P.S.N.).

PII: S1078-1439(09)00092-1

doi: 10.1016/j.urolonc.2009.03.016

Urologic Oncology: Seminars and Original Investigations
Volume 27, Issue 3 , Pages 251-257 , May 2009