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New Targeted Approach to CRPC

  • Takeo Kosaka
  • Mototsugu Oya
Chapter

Abstract

Our understanding of the heterogeneity and genetic characteristics of CRPC demonstrates underlying their complexity, which has been thought to be associated with their intractability. Recent advance of integrative next generation sequencing unveiled the extensive mutational landscape of metastatic CRPC, many of which can be a targetable mutation and been linked to ongoing clinical trials. Molecular stratification of patient groups will clearly be critical to successful drug development and clinical trials from the view point of precision medicine. In this review, we discuss the potential of new targeted approach to impact the clinical management of CRPC.

Keywords

CRPC AR signaling pathway PI3K-PTEN-AKT-mTOR pathway DNA repair pathway WNT pathway Liquid biopsy Circulating tumor cells Cell-free DNA Precision medicine 

References

  1. 1.
    Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.CrossRefGoogle Scholar
  2. 2.
    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;68:4447–54.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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;178:1282–8; discussion 8–9CrossRefPubMedGoogle Scholar
  4. 4.
    Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ueda T, Bruchovsky N, Sadar MD. Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem. 2002;277:7076–85.CrossRefPubMedGoogle Scholar
  6. 6.
    Robinson D, Van Allen EM, YM W, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ferraldeschi R, Welti J, Luo J, Attard G, de Bono JS. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. 2015;34:1745–57.CrossRefPubMedGoogle Scholar
  11. 11.
    Wong YN, Ferraldeschi R, Attard G, de Bono J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat Rev Clin Oncol. 2014;11:365–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Romanel A, Gasi Tandefelt D, Conteduca V, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7:312re10.CrossRefPubMedGoogle Scholar
  13. 13.
    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;10:7121–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Basch E, Autio K, Ryan CJ, et al. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol. 2013;14:1193–9.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fizazi K, Scher HI, Molina A, et al. 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;13:983–92.CrossRefPubMedGoogle Scholar
  17. 17.
    Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.CrossRefGoogle Scholar
  18. 18.
    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;28:1481–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–24.CrossRefPubMedGoogle Scholar
  20. 20.
    Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192–202.CrossRefPubMedGoogle Scholar
  21. 21.
    Kosaka T, Miyajima A, Nagata H, Maeda T, Kikuchi E, Oya M. Human castration resistant prostate cancer rather prefer to decreased 5alpha-reductase activity. Sci Rep. 2013;3:1268.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chuu CP, Kokontis JM, Hiipakka RA, et al. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer. J Biomed Sci. 2011;18:63.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kokontis JM, Lin HP, Jiang SS, et al. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2. PLoS One. 2014;9:e109170.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Umekita Y, Hiipakka RA, Kokontis JM, Liao S. Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride. Proc Natl Acad Sci U S A. 1996;93:11802–7.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Schweizer MT, Wang H, Luber B, et al. Bipolar androgen therapy for men with androgen ablation naive prostate cancer: results from the Phase II BATMAN Study. Prostate. 2016;76:1218–26.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Statz CM, Patterson SE, Mockus SM. mTOR inhibitors in castration-resistant prostate cancer: a systematic review. Target Oncol. 2017;12:47–59.CrossRefPubMedGoogle Scholar
  28. 28.
    Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl. 2014;16:378–86.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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-AKT-dependent way. Prostate. 2013;73:267–77.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yasumizu Y, Miyajima A, Kosaka T, Miyazaki Y, Kikuchi E, Oya M. Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer. J Urol. 2014;191:227–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Kosaka T, Miyajima A, Shirotake S, Suzuki E, Kikuchi E, Oya M. Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer. J Urol. 2011;185:2376–81.CrossRefGoogle Scholar
  33. 33.
    Schwartz S, Wongvipat J, Trigwell CB, et al. Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell. 2015;27:109–22.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Beltran H. DNA mismatch repair in prostate cancer. J Clin Oncol. 2013;31:1782–4.CrossRefGoogle Scholar
  35. 35.
    Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and Olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Brenner JC, Ateeq B, Li Y, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011;19:664–78.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Han S, Brenner JC, Sabolch A, et al. Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. Neoplasia (New York, NY). 2013;15:1207–17.CrossRefGoogle Scholar
  39. 39.
    Feng FY, Brenner JC, Hussain M, Chinnaiyan AM. Molecular pathways: targeting ETS gene fusions in cancer. Clin Cancer Res. 2014;20:4442–8.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2:1134–49.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wang D, Li C, Zhang Y, et al. Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol Oncol. 2016;142:548–56.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang D, Wang M, Jiang N, et al. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget. 2016;7:13153–66.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Ciccarese C, Massari F, Iacovelli R, et al. Prostate cancer heterogeneity: discovering novel molecular targets for therapy. Cancer Treat Rev. 2017;54:68–73.CrossRefPubMedGoogle Scholar
  44. 44.
    Grasso CS, YM W, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13:513–32.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Takebe N, Miele L, Harris PJ, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12:445–64.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kypta RM, Waxman J. Wnt/beta-catenin signalling in prostate cancer. Nat Rev Urol. 2012;9:418–28.CrossRefPubMedGoogle Scholar
  48. 48.
    Cristobal I, Rojo F, Madoz-Gurpide J, Garcia-Foncillas J. Cross talk between Wnt/beta-catenin and CIP2A/Plk1 signaling in prostate cancer: promising therapeutic implications. Mol Cell Biol. 2016;36:1734–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Terry S, Yang X, Chen MW, Vacherot F, Buttyan R. Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. J Cell Biochem. 2006;99:402–10.CrossRefPubMedGoogle Scholar
  50. 50.
    Pantel K, Alix-Panabieres C. The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. Cancer Discov. 2012;2:974–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Frenel JS, Carreira S, Goodall J, et al. Serial next-generation sequencing of circulating cell-free DNA evaluating tumor clone response to molecularly targeted drug administration. Clin Cancer Res. 2015;21:4586–96.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Jiang R, YT L, Ho H, et al. A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer. Oncotarget. 2015;6:44781–93.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Punnoose EA, Ferraldeschi R, Szafer-Glusman E, et al. PTEN loss in circulating tumour cells correlates with PTEN loss in fresh tumour tissue from castration-resistant prostate cancer patients. Br J Cancer. 2015;113:1225–33.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hegemann M, Stenzl A, Bedke J, Chi KN, Black PC, Todenhofer T. Liquid biopsy: ready to guide therapy in advanced prostate cancer? BJU Int. 2016;118:855–63.CrossRefPubMedGoogle Scholar
  55. 55.
    Lallous N, Volik SV, Awrey S, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    McDaniel AS, Ferraldeschi R, Krupa R, et al. Phenotypic diversity of circulating tumour cells in patients with metastatic castration-resistant prostate cancer. BJU Int. 2017;120(5B):E30–44.CrossRefPubMedGoogle Scholar
  57. 57.
    Wyatt AW, Azad AA, Volik SV, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1598–606.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Yap TA, Smith AD, Ferraldeschi R, Al-Lazikani B, Workman P, de Bono JS. Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discov. 2016;15:699–718.CrossRefPubMedGoogle Scholar
  59. 59.
    Barbieri CE, Chinnaiyan AM, Lerner SP, Swanton C, Rubin MA. The emergence of precision urologic oncology: a collaborative review on biomarker-driven therapeutics. Eur Urol. 2017;71:237–46.CrossRefPubMedGoogle Scholar
  60. 60.
    Goodall J, Mateo J, Yuan W, et al. Circulating free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov. 2017;7:1006.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Takeo Kosaka
    • 1
  • Mototsugu Oya
    • 1
  1. 1.Department of UrologyKeio University School of MedicineTokyoJapan

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