Preview

Siberian journal of oncology

Advanced search

MAIN MOLECULAR TARGETS FOR PROSTATE CANCER THERAPY

Abstract

Androgenic pathway plays a pivotal role in the development of benign and malignant prostate tumors. Most of the prostate neoplasms are hormone-dependent at the time of diagnosis. Therapeutic interventions aimed at reducing the level of testosterone in the blood allow to stop progression of the disease. But over time, the tumor almost inevitably starts to progress, moving in the castration-resistant state (CRPC), representing a serious problem of oncourology. In recent years, the possibility of CRRPC therapy increased significantly – there was developed a number of new drugs that effectively inhibit the development of castration-resistant tumors and significantly push back the start of chemotherapy. This review describes the major drug targets and mechanisms of action of abiraterone, enzalutamide, galeterone, VT-464 and other approved and promising CRPC therapies.

About the Authors

G. S. Krasnov
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, Moscow V. N. Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, Moscow
Russian Federation
32, Vavilova Street, 119991-Moscow


A. A. Dmitriev
P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, Moscow V. N. Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, Moscow
Russian Federation


N. N. Volchenko
V. N. Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, Moscow
Russian Federation


T. V. Danilova
V. N. Orekhovich Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences, Moscow
Russian Federation


A. F. Sadritdinova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


A. V. Snezhkina
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


N. V. Melnikova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


M. S. Fedorova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


V. A. Lakunina
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


A. A. Belova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow
Russian Federation


B. Y. Alekseev
P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, Moscow
Russian Federation


A. D. Kaprin
P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, Moscow
Russian Federation


A. V. Kudryavtseva
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, Moscow
Russian Federation


References

1. Antonarakis E.S., Lu C., Wang H., Luber B., Nakazawa M., Roeser J.C., Chen Y., Mohammad T.A., Chen Y., Fedor H.L., Lotan T.L., Zheng Q., De Marzo A.M., Isaacs J.T., Isaacs W.B., Nadal R., Paller C.J., Denmeade S.R., Carducci M.A., Eisenberger M.A., Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer // N. Engl. J. Med. 2014. Vol. 371 (11). P. 1028–1038. doi: 10.1056/NEJMoa1315815.

2. Askew E.B., Gampe R.T. Jr., Stanley T.B., Faggart J.L., Wilson E.M. Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone // J. Biol. Chem. 2007. Vol. 282 (35): P. 25801–25816.

3. Attar R.M., Jure-Kunkel M., Balog A., Cvijic M.E., Dell-John J., Rizzo C.A., Schweizer L., Spires T.E., Platero J.S., Obermeier M., Shan W., Salvati M.E., Foster W.R., Dinchuk J., Chen S.J., Vite G., Kramer R., Gottardis M.M. Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer // Cancer Res. 2009. Vol. 69 (16). P. 6522–6530. doi: 10.1158/0008-5472. CAN-09-1111.

4. Balbas M.D., Evans M.J., Hosfield D.J., Wongvipat J., Arora V.K., Watson P.A., Chen Y., Greene G.L., Shen Y., Sawyers C.L. Overcoming mutation-based resistance to antiandrogens with rational drug design // Elife. 2013. Vol. 2. P. e00499. doi: 10.7554/eLife.00499.

5. Beer T.M., Armstrong A.J., Rathkopf D.E., Loriot Y., Sternberg C.N., Higano C.S., Iversen P., Bhattacharya S., Carles J., Chowdhury S., Davis I.D., de Bono J.S., Evans C.P., Fizazi K., Joshua A.M., Kim C.S., Kimura G., Mainwaring P., Mansbach H., Miller K., Noonberg S.B., Perabo F., Phung D., Saad F., Scher H.I., Taplin M.E., Venner P.M., Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy // N. Engl. J. Med. 2014. Vol. 371 (5). P. 424–433. doi: 10.1056/NEJMoa1405095.

6. Beer T.M., El-Geneidi M., Eilers K.M. Docetaxel (taxotere) in the treatment of prostate cancer // Expert Rev. Anticancer Ther. 2003. Vol. 3 (3). P. 261–268.

7. Bluemn E.G., Nelson P.S. The androgen/androgen receptor axis in prostate cancer // Curr. Opin. Oncol. 2012. Vol. 24 (3). P. 251–257. doi: 10.1097/CCO.0b013e32835105b3.

8. Center M.M., Jemal A., Lortet-Tieulent J., Ward E., Ferlay J., Brawley O., Bray F. International variation in prostate cancer incidence and mortality rates // Eur. Urol. 2012. Vol. 61 (6): P. 1079–1092. doi: 10.1016/j.eururo.2012.02.054.

9. Chang K.H., Li R., Papari-Zareei M., Watumull L., Zhao Y.D., Auchus R.J., Sharifi N. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer // Proc. Natl. Acad. Sci. USA. 2011. Vol. 108 (33). P. 13728-33. doi: 10.1073/pnas.1107898108.

10. Claessens F., Denayer S., Van Tilborgh N., Kerkhofs S., Helsen C., Haelens A. Diverse roles of androgen receptor (AR) domains in ARmediated signaling // Nucl. Recept Signal. 2008. 6. P. e008. doi: 10.1621/ nrs.06008.

11. Cohen Y.C., Liu K.S., Heyden N.L., Carides A.D., Anderson K.M., Daifotis A.G., Gann P.H. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial // J. Natl. Cancer Inst. 2007. Vol. 99 (18). P. 1366–1374.

12. Results from a phase 3, randomized, double-blind, multicenter, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy (ELM-PC 5 Trial) // Clin. Adv. Hematol. Oncol. 2014. Vol. 12 (4 Suppl. 11): P. 6–7.

13. Fang Y., A.E. Fliss, Robins D.M., Caplan A.J. Hsp90 regulates androgen receptor hormone binding affinity in vivo // J. Biol. Chem. 1996. Vol. 271 (45). P. 28697–28702.

14. Farla P., Hersmus R., Trapman J., Houtsmuller A.B. Antiandrogens prevent stable DNA-binding of the androgen receptor // J. Cell Sci. 2005. 118 (Pt 18). P. 4187–4198.

15. Fix C., Jordan C., Cano P., Walker W.H. Testosterone activates mitogen-activated protein kinase and the cAMP response element binding protein transcription factor in Sertoli cells // Proc. Natl. Acad. Sci. USA. 2004. Vol. 101 (30). P. 10919–10924.

16. Fizazi K., Scher H.I., Molina A., Logothetis C.J., Chi K.N., Jones R.J., Staffurth J.N., North S., Vogelzang N.J., Saad F., Mainwaring P., Harland S., Goodman O.B. Jr., Sternberg C.N., Li J.H., Kheoh T., Haqq C.M., de Bono J.S. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study // Lancet Oncol. 2012. Vol. 13 (10). P. 983–892. doi: 10.1016/S1470-2045- (12)70379-0.

17. Fleshner N.E., Lucia M.S., Egerdie B., Aaron L., Eure G., Nandy I., Black L., Rittmaster R.S. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial // Lancet. 2012. Vol. 379 (9821). P. 1103–1111. doi: 10.1016/S0140- 6736(11)61619-X.

18. Grosse A., Bartsch S., Baniahmad A. Androgen receptor-mediated gene repression // Mol. Cell Endocrinol. 2012. Vol. 352 (1–2). P. 46–56. doi: 10.1016/j.mce.2011.06.032.

19. Hamid A.R., Verhaegh G.W., Smit F.P., van Rijt-van de Westerlo C., Armandari I., Armandari I., Brandt A., Sweep F.C., Sedelaar J.P., Schalken J.A. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation // J. Urol. 2014. pii: S0022-5347(14)04414-0. doi: 10.1016/j.juro.2014.09.021.

20. Hazzalin C.A., Mahadevan L.C. MAPK-regulated transcription: a continuously variable gene switch? // Nat. Rev. Mol. Cell Biol. 2002. 3 (1). P. 30–40.

21. Huggins C.B. Studies on prostatic cancer II: the effects of castration on advanced carcinoma of the prostate gland // Arch. Surg. 1941. Vol. l43 (2). P. 209–223.

22. Joseph J.D., Lu N., Qian J., Sensintaffar J., Shao G., Brigham D., Moon M., Maneval E.C., Chen I., Darimont B., Hager J.H. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509 // Cancer Discov. 2013. Vol. 3 (9). P. 1020–1029. doi: 10.1158/2159-8290.CD-13-0226.

23. Kaplan S.A., Chung D.E., Lee R.K., Scofield S., Te A.E. A 5-year retrospective analysis of 5alpha-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride // Int. J. Clin. Pract. 2012. Vol. 66 (11). P. 1052–1055. doi: 10.1111/j.1742-1241.2012.03010.x.

24. Kawabe M., Shibata M.A., Sano M., Takesada Y., Tamano S., Ito N., Shirai T. Decrease of prostaglandin E2 and 5-bromo-2'-deoxyuridine labeling but not prostate tumor development by indomethacin treatment of rats given 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate // Jpn. J. Cancer Res. 1997. Vol. 88 (4). P. 350–355.

25. Klokk T.I., Kurys P., Elbi C., Nagaich A.K., Hendarwanto A., Slagsvold T., Chang C.Y., Hager G.L., Saatcioglu F. Ligand-specific dynamics of the androgen receptor at its response element in living cells // Mol. Cell Biol. 2007. Vol. 27 (5). P. 1823–1843.

26. Koh E., Noda T., Kanaya J., Namiki M. Differential expression of 17beta-hydroxysteroid dehydrogenase isozyme genes in prostate cancer and noncancer tissues // Prostate. 2002. Vol. 53 (2). P. 154–159.

27. Korpal M., Korn J.M., Gao X., Rakiec D.P., Ruddy D.A., Doshi S., Yuan J., Kovats S.G., Kim S., Cooke V.G., Monahan J.E., Stegmeier F., Roberts T.M., Sellers W.R., Zhou W., Zhu P. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide) // Cancer Discov. 2013. Vol. 3 (9). P. 1030–1043. doi: 10.1158/2159-8290.CD-13-0142.

28. Krishnan A.V., Zhao X.Y., Swami S., Brive L., Peehl D.M., Ely K.R., Feldman D. A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer // Endocrinology. 2002. Vol. 143 (5). P. 1889–1900.

29. Lacy J.M., Kyprianou N. A tale of two trials: The impact of 5alphareductase inhibition on prostate cancer (Review) // Oncol. Lett. 2014. Vol. 8 (4). P. 1391–1396. doi: 10.3892/ol.2014.2388.

30. Li R., Evaul K., Sharma K.K., Chang K.H., Yoshimoto J., Liu J., Auchus R.J., Sharifi N. Abiraterone inhibits 3beta-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer // Clin. Cancer Res. 2012. Vol. 18 (13). P. 3571–3579. doi: 10.1158/1078-0432.CCR-12-0908.

31. Liedtke A.J., Adeniji A.O., Chen M., Byrns M.C., Jin Y., Christianson D.W., Marnett L.J., Penning T.M. Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer // J. Med. Chem. 2013. Vol. 56 (6). P. 2429–2446. doi: 10.1021/jm3017656.

32. Lin T.H., Lee S.O., Niu Y., Xu D., Liang L., Li L., Yeh S.D., Fujimoto N., Yeh S., Chang C. Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9(R) Lead to promotion versus suppression of prostate cancer metastasis // J. Biol Chem. 2013. Vol. 288 (27). P. 19359–19369. doi: 10.1074/jbc.M113.477216.

33. Masiello D., Cheng S., Bubley G.J., Lu M.L., Balk S.P. Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor // J. Biol. Chem. 2002. Vol. 277 (29). P. 26321–26326.

34. Mezynski J., Pezaro C., Bianchini D., Zivi A., Sandhu S., Baikady B., Sarvadikar A., Maier G., Reid A.H., Mulick Cassidy A., Olmos D., Attard G., de Bono J. Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for crossresistance? // Ann. Oncol. 2012. Vol. 23 (11). P. 2943–2947. doi: 10.1093/ annonc/mds119.

35. Montgomery R.B., Mostaghel E.A., Vessella R., Hess D.L., Kalhorn T.F., Higano C.S., True L.D., Nelson P.S. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth // Cancer Res. Vol. 2008. 68 (11). P. 4447–4454. doi: 10.1158/0008-5472.CAN-08-0249.

36. Nickel J.C., Gilling P., Tammela T.L., Morrill B., Wilson T.H., Rittmaster R.S. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS) // BJU Int. 2011. Vol. 108 (3). P. 388–394. doi: 10.1111/j.1464- 410X.2011.10195.x.

37. Oskarsson A., Spatafora C., Tringali C., Andersson A.O. Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs // Prostate. 2014. Vol. 74 (8). P. 839–851. doi: 10.1002/ pros.22801.

38. Payton S. Prostate cancer: mortality unaffected by finasteride treatment // Nat. Rev. Urol. 2013. Vol. 10 (10). P. 551. doi: 10.1038/ nrurol.2013.203.

39. Pinsky P., Parnes H., Ford L. Estimating rates of true high-grade disease in the prostate cancer prevention trial // Cancer Prev. Res. (Phila). 2008. Vol. 1 (3). P. 182–186. doi: 10.1158/1940-6207.CAPR-07-0007.

40. Preston M.A., Wilson K.M., Markt S.C., Ge R., Morash C., Stampfer M.J., Loda M., Giovannucci E., Mucci L.A., Olumi A.F. 5alphaReductase inhibitors and risk of high-grade or lethal prostate cancer // JAMA Intern. Med. 2014. Vol. 174 (8). P. 1301–1307. doi: 10.1001/ jamainternmed.2014.1600.

41. Rafferty S.W., Eisner J.R., Moore W.R., Schotzinger R.J., Hoekstra W.J. Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors // Bioorg. Med. Chem. Lett. 2014. Vol. 24 (11). P. 2444–2447. doi: 10.1016/j.bmcl.2014.04.024.

42. Rathkopf D., Liu G., Carducci M.A., Eisenberger M.A., Anand A., Morris M.J., Slovin S.F., Sasaki Y., Takahashi S., Ozono S., Fung N.K., Cheng S., Gan J., Gottardis M., Obermeier M.T., Reddy J., Zhang S., Vakkalagadda B.J., Alland L., Wilding G., Scher H.I. Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castrationresistant prostate cancer // Clin. Cancer Res. 2011. Vol. 17 (4). P. 880–887. doi: 10.1158/1078-0432.CCR-10-2955.

43. Richards J., Lim A.C., Hay C.W., Taylor A.E., Wingate A., Nowakowska K., Pezaro C., Carreira S., Goodall J., Arlt W., McEwan I.J., de Bono J.S., Attard G. 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. Vol. 72 (9). P. 2176–2182. doi: 10.1158/0008-5472.CAN-11-3980.

44. Sartor A.O., Tangen C.M., Hussain M.H., Eisenberger M.A., Parab M.. Fontana J.A., Chapman R.A., Mills G.M., Raghavan D., Crawford E.D. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426) // Cancer. 2008. Vol. 112 (11). P. 2393–2400. doi: 10.1002/cncr.23473.

45. Saylor P.J. Prostate cancer: The androgen receptor remains front and centre // Natl. Rev. Clin. Oncol. 2013. Vol. 10 (3): P. 126–128. doi: 10.1038/nrclinonc.2013.14.

46. Sharifi N., McPhaul M.J., Auchus R.J. Getting from here to there – mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer // J. Investig. Med. 2010. Vol. 58 (8). P. 938–944. doi: 10.231/JIM.0b013e3181ff6bb8.

47. Small E.J., Halabi S., Dawson N.A., Stadler W.M., Rini B.I., Picus J., Gable P., Torti F.M., Kaplan E., Vogelzang N.J. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583) // J. Clin. Oncol. 2004. Vol. 22 (6). P. 1025–1033.

48. Stanbrough M., Bubley G.J., Ross K., Golub T.R., Rubin M.A., Penning T.M., Febbo P.G., Balk S.P. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer // Cancer Res. 2006. Vol. 66 (5). P. 2815–2825. doi: 10.1158/0008-5472. CAN-05-4000.

49. Suzman D.L., Luber B., Schweizer M.T., Nadal R., Antonarakis E.S. Clinical activity of enzalutamide versus docetaxel in men with castrationresistant prostate cancer progressing after abiraterone // Prostate. 2014. Vol. 74 (13). P. 1278–1285. doi: 10.1002/pros.22844.

50. Thomas L.N., Douglas R.C., Rittmaster R.S., Too C.K. Overexpression of 5 alpha-reductase type 1 increases sensitivity of prostate cancer cells to low concentrations of testosterone // Prostate. 2009. Vol. 69 (6). P. 595–602. doi: 10.1002/pros.20911.

51. Titus M.A., Schell M.J., Lih F.B., Tomer K.B., Mohler J.L. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer // Clin. Cancer Res. 2005. Vol. 11 (13). P. 4653–4657. doi: 10.1158/1078- 0432.CCR-05-0525.

52. Toren P., Kim S., Cordonnier T., Crafter C., Davies B.R., Fazli L., Gleave M.E., Zoubeidi A. Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models // Eur. Urol. 2014. pii: S0302-2838(14)00748-9. doi: 10.1016/j. eururo.2014.08.006.

53. Tran C., Ouk S., Clegg N.J., Chen Y., Watson P.A., Arora V., Wongvipat J., Smith-Jones P.M., Yoo D., Kwon A., Wasielewska T., Welsbie D., Chen C.D., Higano C.S., Beer T.M., Hung D.T., Scher H.I., Jung M.E., Sawyers C.L. Development of a second-generation antiandrogen for treatment of advanced prostate cancer // Science. 2009. Vol. 324 (5928). P. 787–790. doi: 10.1126/science.1168175.

54. van Soest R.J., van Royen M.E., de Morree E.S., Moll J.M., Teubel W., Wiemer E.A., Mathijssen R.H., de Wit R., van Weerden W.M. Crossresistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castrationresistant prostate cancer // Eur. J. Cancer. 2013. Vol. 49 (18). P. 3821–3830. doi: 10.1016/j.ejca.2013.09.026.

55. Yamaoka M., Hara T., Hitaka T., Kaku T., Takeuchi T., Takahashi J., Asahi S., Miki H., Tasaka A., Kusaka M. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys // J. Steroid Biochem. Mol. Biol. 2012. Vol. 129 (3–5). P. 115–128. doi: 10.1016/j.jsbmb.2012.01.001.

56. Yuan X., Cai C., Chen S., Chen S., Yu Z., Balk S.P. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis // Oncogene. 2014. Vol. 33 (22). P. 2815–2825. doi: 10.1038/onc.2013.235.


Review

For citations:


Krasnov G.S., Dmitriev A.A., Volchenko N.N., Danilova T.V., Sadritdinova A.F., Snezhkina A.V., Melnikova N.V., Fedorova M.S., Lakunina V.A., Belova A.A., Alekseev B.Y., Kaprin A.D., Kudryavtseva A.V. MAIN MOLECULAR TARGETS FOR PROSTATE CANCER THERAPY. Siberian journal of oncology. 2014;(6):45-53. (In Russ.)

Views: 2929


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1814-4861 (Print)
ISSN 2312-3168 (Online)