Androgen pathway resistance in prostate cancer and therapeutic implications

Expert Opinion on Pharmacotherapy

Volumn 16, Issue 10, 2015, Pages 1521-1537

  Maughan, Benjamin L ^a   Antonarakis, Emmanuel S ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Androgen receptor; AR V7; Hormone resistance; Metastatic castration resistant prostate cancer; Treatment sequence

Indexed keywords

ABIRATERONE; ANDROGEN; ANDROGEN RECEPTOR; ANTINEOPLASTIC HORMONE AGONISTS AND ANTAGONISTS; ENZALUTAMIDE; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RADIOPHARMACEUTICAL AGENT; ANDROSTANE DERIVATIVE; PHENYLTHIOHYDANTOIN;

ANDROGEN DEPRIVATION THERAPY; ANDROGEN THERAPY; ANGIOGENESIS; CANCER COMBINATION CHEMOTHERAPY; CANCER HORMONE THERAPY; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; CASTRATION RESISTANT PROSTATE CANCER; CLINICAL TRIAL (TOPIC); DRUG EFFICACY; DRUG MECHANISM; GENE AMPLIFICATION; GENE OVEREXPRESSION; HUMAN; MALE; MOLECULAR BIOLOGY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POINT MUTATION; PROTEIN PROCESSING; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TREATMENT RESPONSE; ANALOGS AND DERIVATIVES; DRUG RESISTANCE; GENETICS; METABOLISM; METASTASIS; PATHOLOGY; PROSTATIC NEOPLASMS; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT;

ANDROGENS; ANDROSTENES; DRUG RESISTANCE, NEOPLASM; HUMANS; MALE; NEOPLASM METASTASIS; PHENYLTHIOHYDANTOIN; POINT MUTATION; PROSTATIC NEOPLASMS; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT; PROTEIN SPLICING; RECEPTORS, ANDROGEN; SIGNAL TRANSDUCTION;

EID: 84933557037     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1517/14656566.2015.1055249     Document Type: Review

References (96)

1. Surveillance, Epidemiology, and End Results (SEER) Program Populations (1969-2012) (www.seer.cancer.gov/ popdata); National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released March 2014
2. Beer MT, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424-33
3. Sweeney C, Chen Y-H, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol 2014; 32: 5s
4. Roy AK, Tyagi RK, Song CS, et al. Androgen Receptor: Structural Domains and Functional Dynamics after Ligand-Receptor Interaction. Ann N Y Acad Sci 2001; 949: 44-57
5. Darshan MS, Loftus MS, Thadani-Mulero M, et al. Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer. Cancer Res 2011; 71: 6019-29
6. Edwards J, Krishna NS, Mukherjee R, et al. Amplification of the androgen receptor may not explain the development of androgen-independent prostate cancer. BJU Int 2001; 88: 633-7
7. Linja MJ, Savinainen KJ, Saramaki OR, et al. Amplification and overexpression of androgen receptor gene in hormonerefractory prostate cancer. Cancer Res 2001; 61: 3550-5
8. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010; 42: 668-75
9. Haffner MC, De Marzo AM, Meeker AK, et al. Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?. Clin Cancer Res 2011; 17: 3858-64
10. Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study. Sci Transl Med 2015; 7: 269ra2
11. RE-sensitizing with supraphysiologic testosterone to overcome resistance to abiraterone and enzalutamide (The RESTORE Study). Available from: https: //clinicaltrials.gov/ct2/show/ NCT02090114
12. Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance (TRANSFORMER). Available from: https: //clinicaltrials.gov/ct2/show/ NCT02286921
13. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Can Res 2008; 68: 4447-54
14. Mohler JL, Gregory CW, Ford OH, et al. The androgen axis in recurrent prostate cancer. Clin Can Res 2004; 10: 440-8
15. Knuuttila M, Yatkin E, Kallio J, et al. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. Am J Pathol 2014; 184: 2163-73
16. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral De novo steroidogenesis during progression of castration-resistant prostate cancer. Can Res 2008; 68: 6407-15
17. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Eng J Med 2014; 37: 424-33
18. Ryan CJ, Smith MR, De Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 10: 138-48
19. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-97
20. De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995-2005
21. Efstathiou E, Titus M, Tsavachidou D, et al. Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer. JCO 2011; 6: 637-43
22. Efstathiou E, Titus M, Wen S, et al. Molecular characterization of enzalutamide-Treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 1: 53-60
23. Antonarakis ES. Predicting treatment response in castration-resistant prostate cancer: could androgen receptor variant-7 hold the key?. Expert Rev Anticancer Ther 2014; 15: 143-5
24. Nadiminty N, Tummala R, Liu C, et al. NF-kB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther 2013; 12: 1629-37
25. Mostaghel EA, Marck BT, Plymate SR, 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: 5913-25
26. Hu R, Lu C, Mostaghel EA, et al. Distinct transcriptional programs mediated by the ligand-dependent fulllength androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 2012; 72: 3457-62
27. Li Y, Chan SC, Brand LJ, et al. Androgen receptor splice variants mediate enzalutamide resistance in castrationresistant prostate cancer cell lines. Cancer Res 2013; 73: 483-9
28. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028-38
29. Development of circulating molecular predictors of chemotherapy and novel hormonal therapy benefit in men with metastatic castration resistant prostate cancer (mCRPC). Available from: https: //clinicaltrials.gov/ct2/show/ NCT02269982
30. Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castrationresistant prostate cancer. JAMA Oncology 2015; doi: 10.1001/jamaoncol.2015.1341
31. Thadani-Mulero M, Portella L, Sun S, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Can Res 2014; 74: 2270-82
32. Mediwala SN, Sun H, Szafran AT, et al. The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKTdependent way. Prostate 2013; 73: 267-77
33. Koochekpour S. Androgen receptor signaling and mutations in prostate cancer. Asian J Androl 2010; 12(5): 639-57
34. McEwan IJ, Hay CW. The impact of point mutations in the human androgen receptor: classification of mutations on the basis of transcriptional activity. PLoS One 2012; 7(3): e32514
35. Gottliet B, Beitel LK, Nadarajah A, et al. The Androgen receptor gene mutations database: 2012. Hum Mut 2012; 33: 887-94
36. Korpal M, Korn JM, Gao X, et al.An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide). Cancer Discov 2013; 3: 1030-43
37. Balbas MD, Evans MJ, Hosfield DJ, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife 2013; 2: e00499
38. Joseph JD, Qian J, Sensintaffar J, et al. A clinically relevant androgen receptor mutation confers resistance to secondgeneration antiandrogens enzalutamide and ARN-509. Cancer Discov 2013; 3: 1020-9
39. Azad AA, Volik SV, Wyatt AW, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castrationresistant prostate cancer. Clin Can Res 2015; 21(10): 2315-24
40. Chen EJ, Sowalsky AG, Gao S, et al. Abiraterone treatment in castrationresistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 2015; 21: 1273-80
41. Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159: 149-53
42. Arora VK, Schenkein E, Murali R, et al. Glucocorticoid Receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013; 155: 1309-22
43. Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-Type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012; 72: 2176-82
44. Carreira S, Romanel A, Goodall J, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med 2014; 6: 254ra125
45. Enzalutamide with or without abiraterone and prednisone in treating patients with castration-resistant metastatic prostate cancer. Available from: https: //clinicaltrials.gov/ct2/show/ NCT01949337
46. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11-22
47. Kinkade CW, Castillio-Martin M, Puzio-Kuter A, et al. Targeting AKT/ mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008; 118: 3051-64
48. Zhang W, Zhu J, Efferson CL, et al. Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a PTEN-deficient mouse model of prostate cancer. Cancer Res 2009; 69: 7466-72
49. 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: 575-86
50. Kruczek K, Ratterman M, Tolzien K, et al. A phase II study evaluating the toxicity and efficacy of single-Agent temsirolimus in chemotherapy-nai've castration-resistant prostate cancer. Br J Cancer 2013; 109: 1711-16
51. Chee KG, Longmate J, Quinn DI, et al. The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clin Genitourin Cancer 2007; 5: 433-7
52. Armstrong AJ, Shen T, Halabi S, et al. A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer. Clin Genitourin Cancer 2013; 11: 397-406
53. Stefanou D, Batistatou A, Kamina S, et al. Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in benign prostatic hyperplasia and prostate cancer. In Vivo 2004; 18(2): 155-60
54. Weidner N, Carroll PR, Flax J, et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143: 401-9
55. Park HS, Hong SK, Oh MM, et al. Synergistic Antitumor effect of NVPBEZ235 and sunitinib on docetaxel resistant human castration-resistant prostate cancer cells. Anticancer Res 2014; 34: 3457-68
56. Michaelson MD, Oudard S, Ou YC, et al. Randomized, placebo controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic castration-resistant prostate cancer. J Clin Oncol 2014; 32: 76-82
57. Meulenbeld HJ, De Bono J, Tagawa ST, et al. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). Cancer Chemother Pharmacol 2013; 72: 909-16
58. Amato RJ, Wilding G, Bubley G, et al. Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-Treated, castrationresistant prostate cancer. Clin Genitourin Cancer 2012; 10: 232-8
59. Templeton AJ, Dutoit V, Cathomas R, et al. Phase 2 trial of single-Agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol 2013; 64: 150-8
60. Coffey K, Robson CN. Regulation of the androgen receptor by post-Translational modifications. J Endocrinol 2012; 215: 221-37
61. Meulenbeld HJ, Bleuse JP, Vinci EM, et al. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int 2013; 111(1): 44-52
62. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 2011; 1: 487-95
63. A Phase II Trial of MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer. Available from: https: //clinicaltrials.gov/ ct2/show/NCT01799278
64. Alisertib, abiraterone acetate and prednisone in treating patients with hormone-resistant prostate cancer. Available from: https: //clinicaltrials.gov/ ct2/show/NCT01848067
65. Heemers HV, Sebo TJ, Debes JD, et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res 2007; 67: 3422-30
66. Santer FR, Hoschele PP, Oh SJ, et al. Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol Cancer Ther 2011; 10: 1644-55
67. Qin J, Lee HJ, Wu SP, et al. Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 2014; 124: 5013-26
68. Obinata D, Takayama K, Urano T, et al. Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer. Int J Cancer 2012; 130: 1021-8
69. Aggarwal R, Halabi S, Kelly WK, et al. The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance). Cancer 2013; 119: 3636-43
70. Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?. Ann Oncol 2012; 23: 2943-7
71. Schweizer MT, Zhou XC, Wang H, et al. The Influence of Prior Abiraterone Treatment on the Clinical Activity of Docetaxel in Men with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2014; 66: 646-52
72. Badrising S, Van Der Noort V, Van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castrationresistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014; 120: 968-75
73. Schrader AJ, Boegemann M, Ohlmann C-H, et al. Enzalutamide in Castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Europ Urol 2014; 65: 30-6
74. Zafeiriou Z, Ferraldeshi R, Omlin AG, et al. Sequencing of docetaxel and abiraterone acetate for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol 2014; 25(Suppl 4): 6360
75. Noonan KL, Sorth S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castrationresistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802-7
76. Azad AA, Eigl BJ, Murray N, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapynaive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol 2015; 67: 23-9
77. Suzman DL, Luber B, Schweizer MT, et al. Clinical activity of enzalutamide versus docetaxel in men with castrationresistant prostate cancer progressing after abiraterone. Prostate 2014; 74: 1278-85
78. Cabazitaxel versus the switch to alternative AR targeted therapy enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) primary resistant patients to abiraterone or Enz (PRIMCAB). Available from: https: //clinicaltrials.gov/ ct2/show/NCT02379390
79. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicenter, randomized, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700-12
80. Phase 3 study of immunotherapy to treat advanced prostate cancer. Available from: https: //clinicaltrials.gov/ct2/show/ NCT01057810
81. Pembrolizumab in treating patients with metastatic castration resistant prostate cancer previously treated with enzalutamide. Available from: https: // clinicaltrials.gov/ct2/show/NCT02312557
82. Combining ipilimumab with abiraterone acetate plus prednisone in chemotherapy and immunotherapy-nai've patients with progressive metastatic castration-resistant prostate cancer. Available from: https: // clinicaltrials.gov/ct2/show/NCT01688492
83. Phase III study of DCVAC added to standard chemotherapy for men with metastatic castration resistant prostate cancer. Available from: https: // clinicaltrials.gov/ct2/show/NCT02111577
84. CYT107 with or without vaccine therapy in treating patients with metastatic hormone-resistant prostate cancer. Available from: https: //clinicaltrials.gov/ ct2/show/NCT01881867
85. PROSTVAC-VF/TRICOM- vaccine for the treatment of metastatic prostate cancer after failing hormone therapy. Available from: https: //clinicaltrials.gov/ ct2/show/NCT00078585
86. A Phase IB Trial With OTX015, a small molecule inhibitor of the bromodomain and extra-Terminal (BET) proteins, in patients with selected advanced solid tumors. Available from: https: // clinicaltrials.gov/ct2/show/NCT02259114
87. Wuyce A, Degenhardt Y, Bai Y, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 2013; 4: 2419-29
88. Asangani IA, Dommeti VL, Wang X, et al. Therapeutic targeting of BET bromodomain proteins in castrationresistant prostate cancer. Nature 2014; 510: 278-82
89. 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: 2348-57
90. Purushottamachar P, Godbole AM, Gediya LK, et al. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor downregulating agents as an approach to treatment of advanced prostate cancer. J Med Chem 2013; 56: 48880-98
91. kwegyir-Afful AK, Ramalingam S, Purushottamachar P, et al. Clinical candidate galeterone (VN/124-1 or TOK-001) induces the degradation of full-length and splice variant androgen receptors in human prostate cancer cell lines via PI3K-Akt-Mdm2 pathway: implications for prostate cancer therapy. Cancer Res 2013; 73(8 Suppl): 1322
92. Taplin ME, Chi KN, Chu F, et al. Galeterone in 4 patient populations of men with CRPC: Results from ARMOR2. Annals of Oncology 2014; 25(suppl-4): iv255-79
93. Roberts J, Dhillon R, Dransfield D, et al. Androgen Receptor Modulation Optimized for Response in Splice Variant (ARMOR3-SV): Randomized, open-label, multicenter, controlled study of galeterone versus enzalutamide (enz) in men expressing AR-V7 splice variant (SV), metastatic castrate resistant prostate cancer (mCRPC). J Clin Oncol 2015; 33(Suppl 7); abstr 259
94. Myung J-K, Banuelos CA, Fernandez JG, et al. An androgen receptor N-Terminal domain antagonist for treating prostate cancer. J Clin Invest 2013; 123: 2948-60
95. Martin SK, Banuelos CA, Sadar MD, et al. N-Terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. Mol Oncol 2015; 9: 628-39
96. Montgomery RB, Antonarkis ES, Hussain M, et al. A phase 1/2 open-label study of safety and antitumor activity of EPI-506, a novel AR N-Terminal domain inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) with progression after enzalutamide or abiraterone. J Clin Oncol 2015; 33(Suppl); abstr TPS5072