1932

Abstract

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

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2020-01-27
2024-10-12
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Literature Cited

  1. 1. 
    Huggins C, Hodges CV. 1941. Studies on prostate cancer, I: the effect of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1:293–97
    [Google Scholar]
  2. 2. 
    Tolis G, Ackman D, Stellos A et al. 1982. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. PNAS 79:1658–62
    [Google Scholar]
  3. 3. 
    Sharifi N, Gulley JL, Dahut WL 2010. An update on androgen deprivation therapy for prostate cancer. Endocr. Relat. Cancer 17:R305–15
    [Google Scholar]
  4. 4. 
    Geller J, Albert J, Loza D et al. 1978. DHT concentrations in human prostate cancer tissue. J. Clin. Endocrinol. Metab. 46:440–44
    [Google Scholar]
  5. 5. 
    Schroder FH. 2008. Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. Eur. Urol. 53:1129–37
    [Google Scholar]
  6. 6. 
    Sharifi N, Farrar WL. 2006. Androgen receptor as a therapeutic target for androgen independent prostate cancer. Am. J. Ther. 13:166–70
    [Google Scholar]
  7. 7. 
    Dai C, Heemers H, Sharifi N 2017. Androgen signaling in prostate cancer. Cold Spring Harb. Perspect. Med. 7:6351–62
    [Google Scholar]
  8. 8. 
    Trachtenberg J, Pont A. 1984. Ketoconazole therapy for advanced prostate cancer. Lancet 2:433–35
    [Google Scholar]
  9. 9. 
    Eichenberger T, Trachtenberg J. 1988. Effects of high-dose ketoconazole in patients with androgen-independent prostatic cancer. Am. J. Clin. Oncol. 11:Suppl. 2S104–7
    [Google Scholar]
  10. 10. 
    Prostate Cancer Trialists’ Collab. Group 2000. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet. 3551491–98
  11. 11. 
    Labrie F. 1991. Endocrine therapy for prostate cancer. Endocrinol. Metab. Clin. North Am. 20:845–72
    [Google Scholar]
  12. 12. 
    Mousses S, Wagner U, Chen Y et al. 2001. Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20:6718–23
    [Google Scholar]
  13. 13. 
    Holzbeierlein J, Lal P, LaTulippe E et al. 2004. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 164:217–27
    [Google Scholar]
  14. 14. 
    Tomlins SA, Rhodes DR, Perner S et al. 2005. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–48
    [Google Scholar]
  15. 15. 
    Chen CD, Welsbie DS, Tran C et al. 2004. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 10:33–39
    [Google Scholar]
  16. 16. 
    Zhu Z, Chung YM, Sergeeva O et al. 2018. Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging. J. Biol. Chem. 293:17829–37
    [Google Scholar]
  17. 17. 
    Veldscholte J, Ris-Stalpers C, Kuiper GG et al. 1990. 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. 173:534–40
    [Google Scholar]
  18. 18. 
    Taplin ME, Bubley GJ, Ko YJ et al. 1999. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59:2511–15
    [Google Scholar]
  19. 19. 
    Liu S, Kumari S, Hu Q et al. 2017. A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer. eLife 6:e33738
    [Google Scholar]
  20. 20. 
    Dehm SM, Schmidt LJ, Heemers HV et al. 2008. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 68:5469–77
    [Google Scholar]
  21. 21. 
    Hu R, Dunn TA, Wei S et al. 2009. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69:16–22
    [Google Scholar]
  22. 22. 
    Antonarakis ES, Lu C, Wang H et al. 2014. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371:1028–38
    [Google Scholar]
  23. 23. 
    Abida W, Cyrta J, Heller G et al. 2019. Genomic correlates of clinical outcome in advanced prostate cancer. PNAS 116:11428–436
    [Google Scholar]
  24. 24. 
    Titus MA, Schell MJ, Lih FB et al. 2005. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11:4653–57
    [Google Scholar]
  25. 25. 
    Montgomery RB, Mostaghel EA, Vessella R et al. 2008. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447–54
    [Google Scholar]
  26. 26. 
    Sharifi N. 2013. Minireview: androgen metabolism in castration-resistant prostate cancer. Mol. Endocrinol. 27:708–14
    [Google Scholar]
  27. 27. 
    Stanbrough M, Bubley GJ, Ross K et al. 2006. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66:2815–25
    [Google Scholar]
  28. 28. 
    Mitsiades N, Sung CC, Schultz N et al. 2012. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res 72:6142–52
    [Google Scholar]
  29. 29. 
    Lorence MC, Murry BA, Trant JM, Mason JI 1990. Human 3β-hydroxysteroid dehydrogenase/δ5→4isomerase from placenta: expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 126.2493–98
    [Google Scholar]
  30. 30. 
    Evaul K, Li R, Papari-Zareei M et al. 2010. 3β-Hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer. Endocrinology 151:3514–20
    [Google Scholar]
  31. 31. 
    Sharifi N, Auchus RJ. 2012. Steroid biosynthesis and prostate cancer. Steroids 77:719–26
    [Google Scholar]
  32. 32. 
    Simard J, Ricketts ML, Gingras S et al. 2005. Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ54 isomerase gene family. Endocr. Rev. 26.525–82
    [Google Scholar]
  33. 33. 
    Hettel D, Zhang A, Alyamani M et al. 2018. AR signaling in prostate cancer regulates a feed-forward mechanism of androgen synthesis by way of HSD3B1 upregulation. Endocrinology 159:2884–90
    [Google Scholar]
  34. 34. 
    Chang KH, Li R, Kuri B et al. 2013. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154:1074–84
    [Google Scholar]
  35. 35. 
    Sabharwal N, Sharifi N. 2019. HSD3B1 genotypes conferring adrenal restrictive and adrenal permissive phenotypes in prostate cancer and beyond. Endocrinology 160:2180–88
    [Google Scholar]
  36. 36. 
    Hearn JWD, AbuAli G, Reichard CA et al. 2016. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol 17:1435–44
    [Google Scholar]
  37. 37. 
    Agarwal N, Hahn AW, Gill DM et al. 2017. Independent validation of effect of HSD3B1 genotype on response to androgen-deprivation therapy in prostate cancer. JAMA Oncol 3:856–57
    [Google Scholar]
  38. 38. 
    Hearn JWD, Xie W, Nakabayashi M et al. 2018. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol 4:558–62
    [Google Scholar]
  39. 39. 
    Shiota M, Narita S, Akamatsu S et al. 2019. Association of missense polymorphism in HSD3B1 with outcomes among men with prostate cancer treated with androgen-deprivation therapy or abiraterone. JAMA Netw. Open. 2:e190115
    [Google Scholar]
  40. 40. 
    Garcia Gil S, Ramos Rodriguez R, Plata Bello A et al. 2018. Relationship between mutations in the HSD3B1 gene and response time to androgen deprivation therapy in the treatment of prostate cancer. Eur. J. Oncol. Pharmacy 1:3S14–65 107 Poster, Board 008
    [Google Scholar]
  41. 41. 
    Hearn JW, Sweeney CJ, Almassi N et al. 2019. HSD3B1 and overall survival (OS) in men with low-volume (LV) metastatic prostate cancer (PrCa) treated with androgen deprivation therapy (ADT) or chemohormonal therapy in the CHAARTED randomized trial Paper presented at ASCO Annual Meeting Chicago, IL:
    [Google Scholar]
  42. 42. 
    Almassi N, Reichard C, Li J et al. 2018. HSD3B1 and response to a nonsteroidal CYP17A1 inhibitor in castration-resistant prostate cancer. JAMA Oncol 4:554–57
    [Google Scholar]
  43. 43. 
    Alyamani M, Emamekhoo H, Park S et al. 2018. HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J. Clin. Investig. 128:3333–40
    [Google Scholar]
  44. 44. 
    Arora VK, Schenkein E, Murali R et al. 2013. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155:1309–22
    [Google Scholar]
  45. 45. 
    Isikbay M, Otto K, Kregel S et al. 2014. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm. Cancer 5:72–89
    [Google Scholar]
  46. 46. 
    Sharifi N. 2014. Steroid receptors aplenty in prostate cancer. N. Engl. J. Med. 370:970–71
    [Google Scholar]
  47. 47. 
    Obradovic MMS, Hamelin B, Manevski N et al. 2019. Glucocorticoids promote breast cancer metastasis. Nature 567:540–44
    [Google Scholar]
  48. 48. 
    Chapman K, Holmes M, Seckl J 2013. 11β-Hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol. Rev. 93:1139–206
    [Google Scholar]
  49. 49. 
    Li J, Alyamani M, Zhang A et al. 2017. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer. eLife 6:e20183
    [Google Scholar]
  50. 50. 
    Rege J, Nakamura Y, Satoh F et al. 2013. Liquid chromatography–tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J. Clin. Endocrinol. Metab. 98:1182–88
    [Google Scholar]
  51. 51. 
    Rege J, Turcu AF, Kasa-Vubu JZ et al. 2018. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. J. Clin. Endocrinol. Metab. 103:4589–98
    [Google Scholar]
  52. 52. 
    Turcu AF, Nanba AT, Chomic R et al. 2016. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur. J. Endocrinol. 174:601–9
    [Google Scholar]
  53. 53. 
    Campana C, Rege J, Turcu AF et al. 2016. Development of a novel cell based androgen screening model. J. Steroid Biochem. Mol. Biol. 156:17–22
    [Google Scholar]
  54. 54. 
    Storbeck KH, Bloem LM, Africander D et al. 2013. 11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer?. Mol. Cell Endocrinol. 377:135–46
    [Google Scholar]
  55. 55. 
    du Toit T, Bloem LM, Quanson JL et al. 2017. Profiling adrenal 11β-hydroxyandrostenedione metabolites in prostate cancer cells, tissue and plasma: UPC2-MS/MS quantification of 11β-hydroxytestosterone, 11keto-testosterone and 11keto-dihydrotestosterone. J. Steroid Biochem. Mol. Biol. 166:54–67
    [Google Scholar]
  56. 56. 
    Barnard M, Quanson JL, Mostaghel E et al. 2018. 11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): implications for castration resistant prostate cancer. J. Steroid Biochem. Mol. Biol. 183:192–201
    [Google Scholar]
  57. 57. 
    Attard G, Reid AH, Auchus RJ et al. 2012. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J. Clin. Endocrinol. Metab. 97:507–16
    [Google Scholar]
  58. 58. 
    de Bono JS, Logothetis CJ, Molina A et al. 2011. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364:1995–2005
    [Google Scholar]
  59. 59. 
    Ryan CJ, Smith MR, de Bono JS et al. 2013. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368:138–48
    [Google Scholar]
  60. 60. 
    Fizazi K, Tran N, Fein L et al. 2017. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 377:352–60
    [Google Scholar]
  61. 61. 
    James ND, de Bono JS, Spears MR et al. 2017. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377:338–51
    [Google Scholar]
  62. 62. 
    Li Z, Bishop AC, Alyamani M et al. 2015. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523:347–51
    [Google Scholar]
  63. 63. 
    Li Z, Alyamani M, Li J et al. 2016. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer anti-androgen therapy. Nature 533:547–51
    [Google Scholar]
  64. 64. 
    Alyamani M, Li Z, Berk M et al. 2017. Steroidogenic metabolism of galeterone reveals a diversity of biochemical activities. Cell Chem. Biol. 24:825–32
    [Google Scholar]
  65. 65. 
    Tran C, Ouk S, Clegg NJ et al. 2009. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324:787–90
    [Google Scholar]
  66. 66. 
    Scher HI, Beer TM, Higano CS et al. 2010. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375:1437–46
    [Google Scholar]
  67. 67. 
    Clegg NJ, Wongvipat J, Joseph JD et al. 2012. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72:1494–503
    [Google Scholar]
  68. 68. 
    Scher HI, Fizazi K, Saad F et al. 2012. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367:1187–97
    [Google Scholar]
  69. 69. 
    Beer TM, Armstrong AJ, Rathkopf DE et al. 2014. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371:424–33
    [Google Scholar]
  70. 70. 
    Smith MR, Yu MK, Small EJ 2018. Apalutamide and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378:2541–42
    [Google Scholar]
  71. 71. 
    Hussain M, Fizazi K, Saad F et al. 2018. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378:2465–74
    [Google Scholar]
  72. 72. 
    Fizazi K, Shore N, Tammela TL et al. 2019. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 380:1235–46
    [Google Scholar]
  73. 73. 
    Davis ID, Martin AJ, Stockler MR et al. 2019. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl. J. Med. 381:121–31
    [Google Scholar]
  74. 74. 
    Chi KN, Agarwal N, Bjartell A et al. 2019. Apalutamide for metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 381:13–24
    [Google Scholar]
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