Molecular Biology of Novel Targets Identified Through Study of Castration-Recurrent Prostate Cancer

  • Philip A. Watson
  • Charles L. Sawyers


Prostate cancer that recurs in men after complete androgen deprivation therapy remains today a lethal disease. Reactivation of androgen receptor (AR) signaling in the setting of castrate levels of androgen is widely accepted to be the dominant factor leading to prostate cancer progression. The mechanisms driving AR activation in clinical castration-recurrent prostate cancer (CRPC) are poorly understood. A number of hypotheses have been put forth to explain castrate-activated AR based on examination of patient material and the use of prostate cancer model systems. AR ligand binding domain mutations that confer gain-of-function properties through expanded use of alternative steroid ligands and overexpression of the non-mutated AR, with or without concurring genomic amplification, are two of the most widely cited hypotheses. Recently, much attention has been paid to the hypothesis that CRPC acquires the capacity to synthesize testosterone directly. Perturbation of AR signaling remains the main therapeutic objective. New drugs currently in clinical trials may offer some improved management of CRPC through antagonism of AR activity or blockage of extratesticular androgen production. Ultimately, the identification of drugs that promote selective AR degradation may have the greatest impact against the continued action of AR in CRPC.


Androgen Receptor Androgen Deprivation Therapy Androgen Receptor Gene Abiraterone Acetate Human Prostate Cancer Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Attard, G., et al. Abiraterone, an oral, irreversible, Cyp450C17 enzyme inhibitor appears to have activity in post-docetaxel castration refractory prostate cancer (CRPC) patients (pts). In European Society for Medical Oncology 2007 Annual Meeting. 2007. Lugano, Switzerland.Google Scholar
  2. Barrie, S.E., et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17–20 lyase). J Steroid Biochem Mol Biol, 1994. 50(5–6): 267–73.PubMedCrossRefGoogle Scholar
  3. Brown, R.S., et al. Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. J Pathol, 2002. 198(2): 237–44.PubMedCrossRefGoogle Scholar
  4. Chang, C.Y., P.J. Walther, and D.P. McDonnell, Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res, 2001. 61(24): 8712–7.PubMedGoogle Scholar
  5. Chen, C.D., et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med, 2004. 10(1): 33–9.PubMedCrossRefGoogle Scholar
  6. Cheng, H., et al. Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res, 2006. 66(21): 10613–20.PubMedCrossRefGoogle Scholar
  7. Clegg, N.J., et al. Development of androgen receptor antagonists with a novel mechanism of action. In Nuclear Receptors: Steroid Sisters. 2008. Whistler, British Columbia: Keystone Symposia.Google Scholar
  8. Culig, Z., et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol, 1993. 7(12): 1541–50.PubMedCrossRefGoogle Scholar
  9. Culig, Z., 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(2): 242–51.PubMedCrossRefGoogle Scholar
  10. Danila, D.C., et al. Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy. In 2008 ASCO Annual Meeting. 2008. Chicago, IL.Google Scholar
  11. Eder, I.E., et al. Inhibition of LncaP prostate cancer cells by means of androgen receptor antisense oligonucleotides. Cancer Gene Ther, 2000. 7(7): 997–1007.PubMedCrossRefGoogle Scholar
  12. Edwards, J., et al. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer, 2003. 89(3): 552–6.PubMedCrossRefGoogle Scholar
  13. Elo, J.P., et al. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol. J Clin Endocrinol Metab, 1995. 80(12): 3494–500.PubMedCrossRefGoogle Scholar
  14. Evans, B.A., et al. Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation polymorphism analysis. Prostate, 1996. 28(3): 162–71.PubMedCrossRefGoogle Scholar
  15. Ford, O.H. III, et al. Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol, 2003. 170(5): 1817–21.PubMedCrossRefGoogle Scholar
  16. Gaddipati, J.P., et al. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res, 1994. 54(11): 2861–4.PubMedGoogle Scholar
  17. Haag, P., et al. Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol, 2005. 96(3–4): 251–8.PubMedCrossRefGoogle Scholar
  18. Haapala, K., et al. Androgen receptor alterations in prostate cancer relapsed during a combined androgen blockade by orchiectomy and bicalutamide. Lab Invest, 2001. 81(12): 1647–51.PubMedCrossRefGoogle Scholar
  19. Hara, T., et al. Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline. Cancer Res, 2003. 63(17): 5622–8.PubMedGoogle Scholar
  20. Hara, T., et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res, 2003. 63(1): 149–53.PubMedGoogle Scholar
  21. Hellerstedt, B.A. and K.J. Pienta. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin, 2002. 52(3): 154-79.PubMedCrossRefGoogle Scholar
  22. Horoszewicz, J.S., et al. The LNCaP cell line–a new model for studies on human prostatic carcinoma. Prog Clin Biol Res, 1980. 37: 115–32.PubMedGoogle Scholar
  23. Holzbeierlein, J., 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(1): 217–27.PubMedCrossRefGoogle Scholar
  24. Horoszewicz, J.S., et al. LNCaP model of human prostatic carcinoma. Cancer Res, 1983. 43(4): 1809–18.PubMedGoogle Scholar
  25. Huggins, C. and C.V. Hodges. The effect of castration, estogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res, 1941. 1: 293–297.Google Scholar
  26. Hyytinen, E.R., et al. Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer. Lab Invest, 2002. 82(11): 1591–8.PubMedGoogle Scholar
  27. Kaltz-Wittmer, C., et al. FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy. Lab Invest, 2000. 80(9): 1455–64.PubMedCrossRefGoogle Scholar
  28. Klein, K.A., et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med, 1997. 3(4): 402–8.PubMedCrossRefGoogle Scholar
  29. Koivisto, P., et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res, 1997. 57(2): 314–9.PubMedGoogle Scholar
  30. Krishnan, A.V., et al. A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer. Endocrinology, 2002. 143(5): 1889–900.PubMedCrossRefGoogle Scholar
  31. Labrie, C., A. Belanger, and F. Labrie. Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate. Endocrinology, 1988. 123(3): 1412–7.PubMedCrossRefGoogle Scholar
  32. Liao, X., et al. Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol Cancer Ther, 2005. 4(4): 505–15.PubMedCrossRefGoogle Scholar
  33. Linja, M.J., et al. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res, 2001. 61(9): 3550–5.PubMedGoogle Scholar
  34. Marcelli, M., et al. Androgen receptor mutations in prostate cancer. Cancer Res, 2000. 60(4): 944–9.PubMedGoogle Scholar
  35. Miller, W.L., R.J. Auchus, and D.H. Geller. The regulation of 17,20 lyase activity. Steroids, 1997. 62(1): 133–42.PubMedCrossRefGoogle Scholar
  36. Miyoshi, Y., et al. Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients. Prostate, 2000. 43(3): 225–32.PubMedCrossRefGoogle Scholar
  37. Mohler, J.L., et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res, 2004. 10(2): 440–8.PubMedCrossRefGoogle Scholar
  38. Montgomery, R.B., et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res, 2008. 68(11): 4447–54.PubMedCrossRefGoogle Scholar
  39. Mostaghel, E.A., et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res, 2007. 67(10): 5033–41.PubMedCrossRefGoogle Scholar
  40. Navone, N.M., et al. Establishment of two human prostate cancer cell lines derived from a single bone metastasis. Clin Cancer Res, 1997. 3(12 Pt 1): 2493–500.PubMedGoogle Scholar
  41. Newmark, J.R., et al. Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci U S A, 1992. 89(14): 6319–23.PubMedCrossRefGoogle Scholar
  42. O'Donnell, A., et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer, 2004. 90(12): 2317–25.PubMedGoogle Scholar
  43. Page, S.T., et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab, 2006. 91: 3850–6PubMedCrossRefGoogle Scholar
  44. Potter, G.A., et al. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem, 1995. 38(13): 2463–71.PubMedCrossRefGoogle Scholar
  45. Pretlow, T.G., et al. Xenografts of primary human prostatic carcinoma. J Natl Cancer Inst, 1993. 85(5): 394–8.PubMedCrossRefGoogle Scholar
  46. Reid, A., et al. Inhibition of androgen synthesis results in a high response rate in castration refractory prostate cancer (CRPC). In European Society for Medical Oncology 2007 Annual Meeting. 2007. Lugano, Switzerland.Google Scholar
  47. Rowlands, M.G., et al. Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem, 1995. 38(21): 4191–7.PubMedCrossRefGoogle Scholar
  48. Ruizeveld de Winter, J.A., et al. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol, 1994. 144(4): 735–46.PubMedGoogle Scholar
  49. Santen, R.J., et al. Site of action of low dose ketoconazole on androgen biosynthesis in men. J Clin Endocrinol Metab, 1983. 57(4): 732–6.PubMedCrossRefGoogle Scholar
  50. Schellhammer, P.F., et al. Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade. J Urol, 1997. 157(5): 1731–5.PubMedCrossRefGoogle Scholar
  51. Scher, H.I. and W.K. Kelly. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol, 1993. 11(8): 1566–72.PubMedGoogle Scholar
  52. Scher, H.I., et al. Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC). In 2008 ASCO Annual Meeting. 2008. Chicago, IL: American Society of Clinical Oncology.Google Scholar
  53. Shah, N.P., et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell, 2002. 2(2): 117–25.PubMedCrossRefGoogle Scholar
  54. Shah, R.B., et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res, 2004. 64(24): 9209–16.PubMedCrossRefGoogle Scholar
  55. Shao, T.C., et al. In vivo preservation of steroid specificity in CWR22 xenografts having a mutated androgen receptor. Prostate, 2003. 57(1): 1–7.PubMedCrossRefGoogle Scholar
  56. Sirotnak, F.M., et al. Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in the treatment of both androgen-dependent and androgen-independent human prostate cancer. Clin Cancer Res, 2002. 8(12): 3870–6.PubMedGoogle Scholar
  57. Small, E.J., et al. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol, 1997. 157(4): 1204–7.PubMedCrossRefGoogle Scholar
  58. Stanbrough, M., et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res, 2006. 66(5): 2815–25.PubMedCrossRefGoogle Scholar
  59. Tan, J., et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol, 1997. 11(4): 450–9.PubMedCrossRefGoogle Scholar
  60. Taplin, M.E., et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol, 2003. 21(14): 2673–8.PubMedCrossRefGoogle Scholar
  61. Taplin, M.E., et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med, 1995. 332(21): 1393–8.PubMedCrossRefGoogle Scholar
  62. Taplin, M.E., et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res, 1999. 59(11): 2511–5.PubMedGoogle Scholar
  63. Thompson, J., et al. Androgen receptor mutations in high-grade prostate cancer before hormonal therapy. Lab Invest, 2003. 83(12): 1709–13.PubMedCrossRefGoogle Scholar
  64. Tilley, W.D., et al. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res, 1996. 2(2): 277–85.PubMedGoogle Scholar
  65. Trump, D.L., et al. High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects. J Clin Oncol, 1989. 7(8): 1093–8.PubMedGoogle Scholar
  66. Veldscholte, J., et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun, 1990. 173(2): 534–40.PubMedCrossRefGoogle Scholar
  67. Veldscholte, J., et al. Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation. Biochemistry, 1992. 31(8): 2393–9.PubMedCrossRefGoogle Scholar
  68. Visakorpi, T., et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet, 1995. 9(4): 401–6.PubMedCrossRefGoogle Scholar
  69. Wainstein, M.A., et al. CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res, 1994. 54(23): 6049–52.PubMedGoogle Scholar
  70. Wallen, M.J., et al. Androgen receptor gene mutations in hormone-refractory prostate cancer. J Pathol, 1999. 189(4): 559–63.PubMedCrossRefGoogle Scholar
  71. Watson, P.A., et al. Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line. Cancer Res, 2005. 65(24): 11565–71.PubMedCrossRefGoogle Scholar
  72. Watson, P.A., et al. Evidence for an androgen receptor threshold dependency in prostate cancer cells with natural androgen receptor overexpression. In 99th Annual Meeting of the American Association for Cancer Research. 2008. San Diego, CA: AACR.Google Scholar
  73. Wright, M.E., M.J. Tsai, and R. Aebersold. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrinol, 2003. 17(9): 1726–37.PubMedCrossRefGoogle Scholar
  74. Yoshida, T., et al. Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res, 2005. 65(21): 9611–6.PubMedCrossRefGoogle Scholar
  75. Yuan, X., et al. Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells. Am J Pathol, 2006. 169(2): 682–96.PubMedCrossRefGoogle Scholar
  76. Zhao, X.Y., et al. Two mutations identified in the androgen receptor of the new human prostate cancer cell line MDA PCa 2a. J Urol, 1999. 162(6): 2192–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Memorial Sloan-Kettering Cancer CenterNew York, NY, USA

Personalised recommendations