Advertisement

Hormone-Based Therapies for Castration-Resistant Prostate Cancer

  • Elahe A. Mostaghel
  • Peter S. Nelson
Chapter

Abstract

Androgen deprivation therapy (ADT) remains the primary treatment modality for patients with metastatic prostate cancer (PCa) but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) over a period of about 18 months, with an ensuing median survival of 1–2 years. Continued activation of androgen receptor (AR) signaling despite suppression of circulating testosterone (T) appears to remain a critical driving force in tumor progression [1]. Accumulating data emphasize that “androgen-independent” or “hormone-refractory” tumors retain a clinically relevant degree of hormone sensitivity and highlight the continued importance of AR axis activity in advanced tumors [2]. Accordingly, therapeutic strategies designed to more effectively ablate androgen signaling are required to improve clinical efficacy and prevent disease progression. Herein, we review AR-dependent mechanisms underlying PCa progression following standard androgen deprivation strategies (summarized in Table 74.1) and discuss the rationale and status of new hormone-based therapies targeting the AR axis, which are currently in clinical and preclinical development (summarized in Table 74.2).

Keywords

Androgen Receptor Androgen Deprivation Therapy Androgen Receptor Expression Androgen Receptor Signaling Androgen Receptor Antagonist 
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.

References

  1. 1.
    Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33–9.PubMedGoogle Scholar
  2. 2.
    Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23(32):8253–61.PubMedGoogle Scholar
  3. 3.
    de Bono JS. Abiraterone acetate improves survival in metastatic castration-resistant prostate cancer: phase III results. 2010 European Society for Medical Oncology, Milan, 2010.Google Scholar
  4. 4.
    Dreicer R, Agus DB, MacVicar GR, MacLean D, Zhang T, Stadler WM. Safety, pharmacokinetics, and efficacy of TAK-700 in castration-resistant, metastatic prostate cancer: a phase I/II, open-label study. Genitourinary cancers symposium, , San Francisco, Feb 2010.Google Scholar
  5. 5.
    Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 2010;375(9724):1437–46.PubMedGoogle Scholar
  6. 6.
    Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–90.PubMedGoogle Scholar
  7. 7.
    Andersen RJ, Mawji NR, Wang J, et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell. 2010;17(6):535–46.PubMedGoogle Scholar
  8. 8.
    Vasaitis T, Belosay A, Schayowitz A, et al. Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 2008;7(8):2348–57.PubMedGoogle Scholar
  9. 9.
    Geller J, Liu J, Albert J, Fay W, Berry CC, Weis P. Relationship between human prostatic epithelial cell protein synthesis and tissue dihydrotestosterone level. Clin Endocrinol (Oxf). 1987;26(2):155–61.Google Scholar
  10. 10.
    Mohler JL, Gregory CW, Ford 3rd OH, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440–8.PubMedGoogle Scholar
  11. 11.
    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(21):7121–6.PubMedGoogle Scholar
  12. 12.
    Page ST, Lin DW, Mostaghel EA, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006;91(10):3850–6.PubMedGoogle Scholar
  13. 13.
    Geller J, Albert J, Loza D, Geller S, Stoeltzing W, de la Vega D. DHT concentrations in human prostate cancer tissue. J Clin Endocrinol Metab. 1978;46(3):440–4.PubMedGoogle Scholar
  14. 14.
    Geller J, Albert J, Yen SS, Geller S, Loza D. Medical castration of males with megestrol acetate and small doses of diethylstilbestrol. J Clin Endocrinol Metab. 1981;52(3):576–80.PubMedGoogle Scholar
  15. 15.
    Liu J, Geller J, Albert J, Kirshner M. Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue. J Clin Endocrinol Metab. 1985;61(1):129–33.PubMedGoogle Scholar
  16. 16.
    Liu J, Albert J, Geller J. Effects of androgen blockade with ketoconazole and megestrol acetate on human prostatic protein patterns. Prostate. 1986;9(2):199–205.PubMedGoogle Scholar
  17. 17.
    Geller J, Albert J. Effects of castration compared with total androgen blockade on tissue dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH). Urol Res. 1987;15(3):151–3.PubMedGoogle Scholar
  18. 18.
    Forti G, Salerno R, Moneti G, et al. Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alpha-reductase activity and androgen receptor content. J Clin Endocrinol Metab. 1989;68(2):461–8.PubMedGoogle Scholar
  19. 19.
    Nishiyama T, Ikarashi T, Hashimoto Y, Wako K, Takahashi K. 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(4 Pt 1):1282–8; discussion 8–9.PubMedGoogle Scholar
  20. 20.
    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(11):4447–54.PubMedGoogle Scholar
  21. 21.
    Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008;22(2):243–58.PubMedGoogle Scholar
  22. 22.
    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(2):765–71.PubMedGoogle Scholar
  23. 23.
    Miyamoto H, Yeh S, Lardy H, Messing E, Chang C. Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci USA. 1998;95(19):11083–8.PubMedGoogle Scholar
  24. 24.
    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(2):242–51.PubMedGoogle Scholar
  25. 25.
    Gregory CW, Johnson Jr RT, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61(7):2892–8.PubMedGoogle Scholar
  26. 26.
    Gregory CW, Hamil KG, Kim D, et al. Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Res. 1998;58(24):5718–24.PubMedGoogle Scholar
  27. 27.
    Mohler JL, Morris TL, Ford 3rd OH, Alvey RF, Sakamoto C, Gregory CW. Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer. Prostate. 2002;51(4):247–55.PubMedGoogle Scholar
  28. 28.
    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(10):5033–41.PubMedGoogle Scholar
  29. 29.
    Greenberg E. Endocrine therapy in the management of prostatic cancer. Clin Endocrinol Metab. 1980;9(2):369–81.PubMedGoogle Scholar
  30. 30.
    Robinson MR, Shearer RJ, Fergusson JD. Adrenal suppression in the treatment of carcinoma of the prostate. Br J Urol. 1974;46(5):555–9.PubMedGoogle Scholar
  31. 31.
    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(2):361–76.PubMedGoogle Scholar
  32. 32.
    Schmitt B, Bennett C, Seidenfeld J, Samson D, Wilt T. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev. 2000;(2):CD001526.Google Scholar
  33. 33.
    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(1):71–8.PubMedGoogle Scholar
  34. 34.
    Small EJ, Ryan CJ. The case for secondary hormonal therapies in the chemotherapy age. J Urol. 2006;176(6 Suppl 1):S66–71.PubMedGoogle Scholar
  35. 35.
    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(5):2815–25.PubMedGoogle Scholar
  36. 36.
    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(1):217–27.PubMedGoogle Scholar
  37. 37.
    Koh E, Kanaya J, Namiki M. Adrenal steroids in human prostatic cancer cell lines. Arch Androl. 2001;46(2):117–25.PubMedGoogle Scholar
  38. 38.
    Mizokami A, Koh E, Izumi K, et al. Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone. Endocr Relat Cancer. 2009;16(4):1139–55.PubMedGoogle Scholar
  39. 39.
    Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407–15.PubMedGoogle Scholar
  40. 40.
    Chang KH, Li R, Papari-Zareei M, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2011;108(33):13728–33.PubMedGoogle Scholar
  41. 41.
    Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab. 2004;15(9):432–8.PubMedGoogle Scholar
  42. 42.
    Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011;71(4):1486–96.PubMedGoogle Scholar
  43. 43.
    Bauman DR, Steckelbroeck S, Williams MV, Peehl DM, Penning TM. Identification of the major oxidative 3{alpha}-hydroxysteroid dehydrogenase in human prostate that converts 5{alpha}-androstane-3{alpha},17{beta}-diol to 5{alpha}-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease. Mol Endocrinol. 2006;20(2):444–58.PubMedGoogle Scholar
  44. 44.
    Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol. 2008;295(1–2):115–20.PubMedGoogle Scholar
  45. 45.
    Locke JA, Wasan KM, Nelson CC, Guns ES, Leon CG. Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A: Cholesterol Acyltransferase (ACAT). Prostate. 2008;68(1):20–33.PubMedGoogle Scholar
  46. 46.
    Locke JA, Nelson CC, Adomat HH, Hendy SC, Gleave ME, Guns ES. Steroidogenesis inhibitors alter but do not eliminate androgen synthesis mechanisms during progression to castration-resistance in LNCaP prostate xenografts. J Steroid Biochem Mol Biol. 2009;115(3–5):126–36. Epub 2009 Apr 5.PubMedGoogle Scholar
  47. 47.
    Leon CG, Locke JA, Adomat HH, et al. Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate. 2009;70(4):390–400.Google Scholar
  48. 48.
    Arnold JT, Gray NE, Jacobowitz K, et al. Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells. J Steroid Biochem Mol Biol. 2008;111(3–5):240–6.PubMedGoogle Scholar
  49. 49.
    Sillat T, Pöllänen R, Lopes JR, et al. Intracrine androgenic apparatus in human bone marrow stromal cells. J Cell Mol Med. 2009;13(9B):3296–302.PubMedGoogle Scholar
  50. 50.
    Wright JL, Kwon EM, Ostrander EA, et al. Expression of SLCO transport genes in castration resistant prostate cancer and impact of genetic variation in SCLO1B3 and SLCO2B1 on prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev. 2011;20(4):619–27. Epub 2011 Jan 25.PubMedGoogle Scholar
  51. 51.
    Zair ZM, Eloranta JJ, Stieger B, Kullak-Ublick GA. Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics. 2008;9(5):597–624.PubMedGoogle Scholar
  52. 52.
    Hamada A, Sissung T, Price DK, et al. Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res. 2008;14(11):3312–8.PubMedGoogle Scholar
  53. 53.
    Sharifi N, Hamada A, Sissung T, et al. A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer. BJU Int. 2008;102(5):617–21.PubMedGoogle Scholar
  54. 54.
    Yang M, Oh WK, Xie W, et al. Genetic variations in SLCO2B1 and SLCO1B3 and the efficacy of androgen-deprivation therapy in prostate cancer patients. J Clin Oncol. 2011;29(18):2565–73.Google Scholar
  55. 55.
    Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9(4):401–6.PubMedGoogle Scholar
  56. 56.
    Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120(8):2715–30.PubMedGoogle Scholar
  57. 57.
    Taplin ME, Balk SP. Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem. 2004;91(3):483–90.PubMedGoogle Scholar
  58. 58.
    Steinkamp MP, O’Mahony OA, Brogley M, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69(10):4434–42.PubMedGoogle Scholar
  59. 59.
    Veldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41(3–8):665–9.PubMedGoogle Scholar
  60. 60.
    Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer. 2007;120:719–33.PubMedGoogle Scholar
  61. 61.
    Zhu P, Baek SH, Bourk EM, et al. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell. 2006;124(3):615–29.PubMedGoogle Scholar
  62. 62.
    Rahman MM, Miyamoto H, Lardy H, Chang C. Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells. Proc Natl Acad Sci USA. 2003;100(9):5124–9.PubMedGoogle Scholar
  63. 63.
    Culig Z. Androgen receptor cross-talk with cell signalling pathways. Growth Factors. 2004;22(3):179–84.PubMedGoogle Scholar
  64. 64.
    Wu JD, Haugk K, Woodke L, Nelson P, Coleman I, Plymate SR. Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J Cell Biochem. 2006;99(2):392–401.PubMedGoogle Scholar
  65. 65.
    Dorff TB, Goldman B, Pinski JK, et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-­pretreated patients with castration-resistant prostate cancer. Clin Cancer Res. 2010;16(11):3028–34.PubMedGoogle Scholar
  66. 66.
    Srebrow A, Kornblihtt AR. The connection between splicing and cancer. J Cell Sci. 2006;119(Pt 13):2635–41.PubMedGoogle Scholar
  67. 67.
    Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69(6):2305–13.PubMedGoogle Scholar
  68. 68.
    Hornberg E, Ylitalo EB, Crnalic S, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One. 2011;6(4):e19059.PubMedGoogle Scholar
  69. 69.
    Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69(1):16–22.PubMedGoogle Scholar
  70. 70.
    Hu R, Isaacs WB, Luo J. A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate. 2011;71(15):1656–67. doi: 10.1002/pros.21382. Epub 2011 Mar 28.PubMedGoogle Scholar
  71. 71.
    Marcias G, Erdmann E, Lapouge G, et al. Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line. Hum Mutat. 2010;31(1):74–80.PubMedGoogle Scholar
  72. 72.
    Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68(13):5469–77.PubMedGoogle Scholar
  73. 73.
    Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci. 2010;107(39):16759–65. Epub 2010 Sep 7.PubMedGoogle Scholar
  74. 74.
    Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM. Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res. 2011;71(6):2108–17.PubMedGoogle Scholar
  75. 75.
    Centenera MM, Harris JM, Tilley WD, Butler LM. The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol. 2008;22(11):2373–82.PubMedGoogle Scholar
  76. 76.
    Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011;185(3):787–94.PubMedGoogle Scholar
  77. 77.
    Morote J, Planas J, Salvador C, Raventos CX, Catalan R, Reventos J. Individual variations of serum testosterone in patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 2009;103(3):332–5; discussion 5.PubMedGoogle Scholar
  78. 78.
    Raddin RS, Walko CM, Whang YE. Response to degarelix after resistance to luteinizing hormone-releasing hormone agonist therapy for metastatic prostate cancer. Anticancer Drugs. 2011;22(3):299–302.PubMedGoogle Scholar
  79. 79.
    Ryan CJ, Halabi S, Ou SS, Vogelzang NJ, Kantoff P, Small EJ. Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study. Clin Cancer Res. 2007;13(7):2030–7.PubMedGoogle Scholar
  80. 80.
    Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337–45.PubMedGoogle Scholar
  81. 81.
    Hashimoto K, Masumori N, Hashimoto J, Takayanagi A, Fukuta F, Tsukamoto T. Serum testosterone level to predict the efficacy of sequential Use of antiandrogens as second-line treatment following androgen deprivation monotherapy in patients with castration-resistant prostate cancer. Jpn J Clin Oncol. 2010;41(3):405–10.PubMedGoogle Scholar
  82. 82.
    Handratta VD, Vasaitis TS, Njar VCO, 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(8):2972–84.PubMedGoogle Scholar
  83. 83.
    O’Donnell A, Judson I, Dowsett M, 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
  84. 84.
    Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27(23):3742–8.PubMedGoogle Scholar
  85. 85.
    Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28):4563–71.PubMedGoogle Scholar
  86. 86.
    Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28(9):1481–8.PubMedGoogle Scholar
  87. 87.
    Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28(9):1489–95.PubMedGoogle Scholar
  88. 88.
    Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496–501.PubMedGoogle Scholar
  89. 89.
    Ryan CJ, Shah SK, Efstathiou E, et al. Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin Cancer Res. 2011;17(14):4854–61. Epub 2011 Jun 1.PubMedGoogle Scholar
  90. 90.
    Bruno RD, Gover TD, Burger AM, Brodie AM, Njar VC. 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol Cancer Ther. 2008;7(9):2828–36.PubMedGoogle Scholar
  91. 91.
    Godoy A, Kawinski E, Li Y, et al. 5alpha-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. Prostate. 2011;71(10):1033–46.PubMedGoogle Scholar
  92. 92.
    Taplin ME, Regan MM, Ko YJ, et al. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15(22):7099–105.PubMedGoogle Scholar
  93. 93.
    Bauman D, Steckelbroeck S, Peehl D, Penning T. Transcript profiling of the androgen signal in normal prostate, benign prostatic hyperplasia and prostate cancer. Endocrinology. 2006;147(12):5806–16. Epub 2006 Sep 7.PubMedGoogle Scholar
  94. 94.
    Ji Q, Chang L, Stanczyk FZ, Ookhtens M, Sherrod A, Stolz A. Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Res. 2007;67(3):1361–9.PubMedGoogle Scholar
  95. 95.
    Bauman DR, Rudnick SI, Szewczuk LM, Jin Y, Gopishetty S, Penning TM. Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes. Mol Pharmacol. 2005;67(1):60–8.PubMedGoogle Scholar
  96. 96.
    Byrns MC, Steckelbroeck S, Penning TM. An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem Pharmacol. 2008;75(2):484–93. Epub 2007 Sep 14.PubMedGoogle Scholar
  97. 97.
    Day JM, Tutill HJ, Purohit A, Reed MJ. Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis. Endocr Relat Cancer. 2008;15(3):665–92.PubMedGoogle Scholar
  98. 98.
    Evaul K, Li R, Papari-Zareei M, Auchus RJ, Sharifi N. 3beta-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer. Endocrinology. 2010;151(8):3514–20.PubMedGoogle Scholar
  99. 99.
    Thomas JL, Bucholtz KM, Kacsoh B. Selective inhibition of human 3beta-hydroxysteroid dehydrogenase type 1 as a potential treatment for breast cancer. J Steroid Biochem Mol Biol. 2011;125(1–2):57–65. Epub 2010 Aug 22.PubMedGoogle Scholar
  100. 100.
    A phase I dose escalating study evaluating the pharmacodynamic profile and safety of BN83495 in patients with prostate cancer with evidence of disease progression while on androgen ablative therapy. ClinicalTrialsgov 2011. 28 Feb 2011. Cited 1 Apr 2011, NCT00790374. Available from http://clinicaltrials.gov/ct2/show/study/NCT00790374?intr=%22BN83495%22&rank=1.
  101. 101.
    Koreckij TD, Trauger RJ, Montgomery RB, et al. HE3235 inhibits growth of castration-resistant prostate cancer. Neoplasia. 2009;11(11):1216–25.PubMedGoogle Scholar
  102. 102.
    Ahlem C, Kennedy M, Page T, et al. 17alpha-Alkynyl 3alpha, 17beta-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism. Invest New Drugs. 2012;30(1):59–78. Epub 2010 Sep 3.PubMedGoogle Scholar
  103. 103.
    Montgomery RB, Morris MJ, Ryan CJ, et al. HE3235, a synthetic adrenal hormone, in patients with castration-resistant prostate cancer (CRPC): clinical phase I/II trial results. Genitourinary cancers symposium, San Francisco, Feb 2010.Google Scholar
  104. 104.
    Liu SV, Schally AV, Hawes D, et al. Expression of receptors for luteinizing hormone-releasing hormone (LH-RH) in prostate cancers following therapy with LH-RH agonists. Clin Cancer Res. 2010;16(18):4675–80.PubMedGoogle Scholar
  105. 105.
    Gnanapragasam V, Darby S, Khan M, Lock W, Robson C, Leung H. Evidence that prostate gonadotropin-releasing hormone receptors mediate an anti-tumourigenic response to analogue therapy in hormone refractory prostate cancer. J Pathol. 2005;206(2):205–13.PubMedGoogle Scholar
  106. 106.
    Emons G, Sindermann H, Engel J, Schally AV, Grundker C. Luteinizing hormone-releasing hormone receptor-targeted chemotherapy using AN-152. Neuroendocrinology. 2009;90(1):15–8.PubMedGoogle Scholar
  107. 107.
    Singh P, Uzgare A, Litvinov I, Denmeade SR, Isaacs JT. Combinatorial androgen receptor targeted therapy for prostate cancer. Endocr Relat Cancer. 2006;13(3):653–66.PubMedGoogle Scholar
  108. 108.
    Leversha MA, Han J, Asgari Z, et al. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res. 2009;15(6):2091–7.PubMedGoogle Scholar
  109. 109.
    Rathkopf D, Liu G, Carducci MA, et al. Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer. Clin Cancer Res. 2011;17(4):880–7.PubMedGoogle Scholar
  110. 110.
    Solit DB, Zheng FF, Drobnjak M, et al. 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res. 2002;8(5):986–93.PubMedGoogle Scholar
  111. 111.
    Welsbie DS, Xu J, Chen Y, et al. Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res. 2009;69(3):958–66.PubMedGoogle Scholar
  112. 112.
    Marrocco DL, Tilley WD, Bianco-Miotto T, et al. Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation. Mol Cancer Ther. 2007;6(1):51–60.PubMedGoogle Scholar
  113. 113.
    Morgan TM, Koreckij TD, Corey E. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 2009;9(2):237–49.PubMedGoogle Scholar
  114. 114.
    Wang Y, Kreisberg JI, Ghosh PM. Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. Curr Cancer Drug Targets. 2007;7(6):591–604.PubMedGoogle Scholar
  115. 115.
    Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575–86.PubMedGoogle Scholar
  116. 116.
    Mulholland DJ, Tran LM, Li Y, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell. 2011;19(6):792–804.PubMedGoogle Scholar
  117. 117.
    Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS, Whang YE. Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 2010;29(22):3208–16.PubMedGoogle Scholar
  118. 118.
    Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer. 2009;101(2):263–8.PubMedGoogle Scholar
  119. 119.
    Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15(23):7421–8.PubMedGoogle Scholar
  120. 120.
    Changmeng C, Balk SP. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71(20):6503–13. Epub 2011 Aug 25.Google Scholar
  121. 121.
    Mostaghel EA, Marck B, Plymate S, et al. Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011;17(18):5913–25. Epub 2011 Aug 1.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • Elahe A. Mostaghel
    • 1
    • 2
  • Peter S. Nelson
    • 1
    • 2
  1. 1.Division of Medical Oncology, Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Division of Clinical ResearchFred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations