Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer

Current Treatment Options in Oncology

Volumn 16, Issue 12, 2015, Pages 1-14

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

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Abiraterone; Androgen receptor variants; AR V7; Castration resistant prostate cancer; Enzalutamide; Hormonal therapy; Resistance; Taxane

Indexed keywords

4 (4 CHLOROPHENYL) N (4 HYDROXYPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETAMIDE; 6 (4 CHLOROPHENYL) N ETHYL 8 METHOXY 1 METHYL 4H [1,2,4]TRIAZOLO[4,3 A][1,4]BENZODIAZEPINE 4 ACETAMIDE; ABIRATERONE; ANTINEOPLASTIC AGENT; CABAZITAXEL; DOCETAXEL; ENZALUTAMIDE; EPI 506; GALETERONE; GS 5829; IPILIMUMAB; NICLOSAMIDE; NIVOLUMAB; TESTOSTERONE; UNCLASSIFIED DRUG; ANDROGEN RECEPTOR; ANDROSTANE DERIVATIVE; AR PROTEIN, HUMAN; BRIDGED COMPOUND; ISOPROTEIN; PHENYLTHIOHYDANTOIN; TAXANE; TAXOID;

ALTERNATIVE RNA SPLICING; AR GENE; CANCER HORMONE THERAPY; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; CASTRATION RESISTANT PROSTATE CANCER; CHEMOSENSITIVITY; DRUG MEGADOSE; GENE EXPRESSION; HUMAN; METASTASIS; MOLECULARLY TARGETED THERAPY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); RECEPTOR GENE; REVIEW; ANALOGS AND DERIVATIVES; DRUG RESISTANCE; GENETICS; MALE; PATHOLOGY; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT;

ANDROSTENES; ANDROSTENOLS; BRIDGED COMPOUNDS; DRUG RESISTANCE, NEOPLASM; HUMANS; MALE; PHENYLTHIOHYDANTOIN; PROSTATIC NEOPLASMS, CASTRATION-RESISTANT; PROTEIN ISOFORMS; RECEPTORS, ANDROGEN; TAXOIDS;

EID: 84946023365     PISSN: 15272729     EISSN: 15346277     Source Type: Journal    
DOI: 10.1007/s11864-015-0375-z     Document Type: Review

References (44)

1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.
2. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–48.
3. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33.
4. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97.
5. Maughan BL, Antonarakis ES. Androgen pathway resistance in prostate cancer and therapeutic implications. Expert Opin Pharmacother. 2015;16(10):1521–37.
6. Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. 2015;67(3):470–9. An excellent review on mechanisms of androgen resistance.
7. 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.
8. Lu C, Luo J. Decoding the androgen receptor splice variants. Transl Androl Urol. 2013;2(3):178–86.
9. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.
10. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, 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.
11. Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72(14):3457–62. Study of the mechanisms of splice variant activity in mCRPC.
12. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, 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.
13. Hornberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, 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.
14. Chan SC, Li Y, Dehm SM. Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem. 2012;287(23):19736–49. Study of the mechanisms of splice variant activity in mCRPC.
15. Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015;5:7654.
16. Li Y, Hwang TH, Oseth LA, Hauge A, Vessella RL, Schmechel SC, et al. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene. 2012;31(45):4759–67.
17. Nakazawa M, Antonarakis ES, Luo J. Androgen receptor splice variants in the era of enzalutamide and abiraterone. Hormone Cancer. 2014;5(5):265–73.
18. Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, et al. NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013;12(8):1629–37.
19. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, 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.
20. Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74(8):2270–82.
21. Zhang G, Liu X, Li J, Ledet E, Alvarez X, Qi Y, et al. Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents. Oncotarget. 2015. doi: 10.18632/oncotarget.4396.
22. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38. First clinical study of AR variant expression in men with mCRPC treated with novel hormonal therapies.
23. Efstathiou E, Titus M, Wen S, Hoang A, Karlou M, Ashe R, et al. Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol. 2015;67(1):53–60. A clinical trial documenting the poor prognosis in patients with AR-V7 expression.
24. Steinestel J, Luedeke M, Arndt A, Schnoeller TJ, Lennerz JK, Wurm C, et al. Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget. 2015.doi: 10.18632/oncotarget.3925.
25. Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1(5):582–91. First clinical study of AR variant expression in men with mCRPC treated with chemotherapy.
26. Onstenk W, Sieuwerts AM, Kraan J, Van M, Nieuweboer AJ, Mathijssen RH, et al. Efficacy of cabazitaxel in castration-resistant prostate cancer is independent of the presence of AR-V7 in circulating tumor cells. Eur Urol. 2015. doi:10.1016/j.eururo.2015.07.007.
27. Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA, et al. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol. 2015;26(9):1859–65. This is a clinical study documenting AR-V7 expression over time, demontsrating the variable nature of AR-V7 expression relative to ongoing treatments.
28. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.
29. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.
30. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.
31. Kwegyir-Afful AK, Senthilmurugan R, Purushottamachar P, Ramamurthy VP, Njar VC. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. Oncotarget. 2015. doi: 10.18632/oncotarget.4578.
32. Taplin ME, Chi KN, Chu F, Cochran J, Edenfield WJ, Eisenberger MA, et al. Galterone in 4 patient populations of men with CRPC: results from ARMOR2. Ann Oncol. 2014;25 Suppl 4:iv255–79. A Clinical trial suggesting activity of a novel hormonal agent in patients with AR-V7 expression.
33. Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, 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.
34. Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, et al. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer. J Med Chem. 2013;56(12):4880–98.
35. Basheer F, Huntly BJ. BET bromodomain inhibitors in leukemia. Exp Hematol. 2015;43(8):718–31.
36. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19(4):523–34.
37. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510(7504):278–82.
38. Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame MC, et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013;4(12):2419–29.
39. Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest. 2013;123(7):2948–60.
40. Martin SK, Banuelos CA, Sadar MD, Kyprianou N. N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. Mol Oncol. 2015;9(3):628–39.
41. Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, 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.
42. Montgomery R, Antonarakis ES, Hussain M, Fizazi K, Joshua AM, Attard G, 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).
43. Liu C, Lou W, Zhu Y, Nadiminty N, Schwartz CT, Evans CP, et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res. 2014;20(12):3198–210.
44. Lu W, Lin C, Roberts MJ, Waud WR, Piazza GA, Li Y. Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/beta-catenin pathway. PLoS One. 2011;6(12):e29290.