Precision Medicine in Castration-Resistant Prostate Cancer

거세저항성전립선암에서 정밀의학에 대한 고찰

  • Kim, Won Tae (Department of Urology, College of Medicine, Chungbuk National University) ;
  • Yun, Seok Joong (Department of Urology, College of Medicine, Chungbuk National University) ;
  • Kim, Wun-Jae (Department of Urology, College of Medicine, Chungbuk National University)
  • 김원태 (충북대학교 의과대학 비뇨의학과교실) ;
  • 윤석중 (충북대학교 의과대학 비뇨의학과교실) ;
  • 김원재 (충북대학교 의과대학 비뇨의학과교실)
  • Received : 2018.11.21
  • Accepted : 2018.12.05
  • Published : 2018.12.30


Prostate cancer is usually managed by androgen deprivation therapy after failure of primary treatment. However, such therapies are only temporarily effective in prostate cancer patients, and the most patients experience the progression to castration-resistant prostate cancer (CRPC). Docetaxel chemotherapy is conventional effective treatment for CRPC but has many adverse effects. In CRPC patients, treatment decisions were not typically base on the recognitions of inter-individual differences. Therefore, there are growing interests for precision medicine in CRPC. In this review, we summarized the precision medicine such as candidate target genes and potential therapies in CRPC.


Supported by : National Research Foundation of Korea (NRF)


  1. Sharifi N, Dahut WL, Steinberg SM, Figg WD, Tarassoff C, Arlen P, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int 2005;96:985-9.
  2. Lowrance WT, Roth BJ, Kirkby E, Murad MH, Cookson MS. Castration-resistant prostate cancer: AUA Guideline Amendment 2015. J Urol 2016;195:1444-52.
  3. Lowrance WT, Murad MH, Oh WK, Jarrard DF, Resnick MJ, Cookson MS. Castration-resistant prostate cancer: AUA Guideline Amendment 2018. J Urol 2018 Aug 4. pii: S0022-5347(18)43671-3. https://doi.og/10.1016/j.juro.2018.07.090.
  4. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.
  5. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20.
  6. McCrea EM, Lee DK, Sissung TM, Figg WD. Precision medicine applications in prostate cancer. Ther Adv Med Oncol 2018;10:1758835918776920.
  7. Huggins C, Hodges CV. The effect of castration, of estrogen and of androgen injection on serum pahosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293-7.
  8. Huggins C, Stevens RE Jr, Hodges CV. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941;43:209-23.
  9. Kim WT, Yun SJ, Kim WJ. The role of microRNAs in oncogenesis and progression of prostate cancer. Korean J Urol Oncol 2018;16:1-6.
  10. Giri VN, Knudsen KE, Kelly WK, Abida W, Andriole GL, Bangma CH, et al. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 2018;36:414-24.
  11. Kirchhoff T, Kauff ND, Mitra N, Nafa K, Huang H, Palmer C, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 2004;10:2918-21.
  12. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443-53.
  13. Song WH, Kim SH, Joung JY, Park WS, Seo HK, Chung J, et al. Prostate cancer in a patient with a family history of BRCA mutation: a case report and literature review. J Korean Med Sci 2017;32:377-81.
  14. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008;105:17079-84.
  15. Balmana J, Tung NM, Isakoff SJ, Grana B, Ryan PD, Saura C, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014;25:1656-63.
  16. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-34.
  17. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244-50.
  18. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697-708.
  19. Genetics of Prostate Cancer (PDQ(R)): Health Professional Version [Internet]. Bethesda (MD): Nathional Cancer Insitute; 2018 [cited 2018 Jun 13]. Available from:
  20. Rosty C, Walsh MD, Lindor NM, Thibodeau SN, Mundt E, Gallinger S, et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer 2014;13:573-82.
  21. Raymond VM, Mukherjee B, Wang F, Huang SC, Stoffel EM, Kastrinos F, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013;31:1713-8.
  22. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-20.
  23. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.
  24. Hansen AR, Massard C, Ott PA, Haas NB, Lopez JS, Ejadi S, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol 2018;29:1807-13.
  25. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017;355:84-8.
  26. Kregel S, Kiriluk KJ, Rosen AM, Cai Y, Reyes EE, Otto KB, et al. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS One 2013;8:e53701.
  27. Jia X, Li X, Xu Y, Zhang S, Mou W, Liu Y, et al. SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J Mol Cell Biol 2011;3:230-8.
  28. Russo MV, Esposito S, Tupone MG, Manzoli L, Airoldi I, Pompa P, et al. SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis. Oncotarget 2016;7:12372-85.
  29. Favaro R, Appolloni I, Pellegatta S, Sanga AB, Pagella P, Gambini E, et al. Sox2 is required to maintain cancer stem cells in a mouse model of high-grade oligodendroglioma. Cancer Res 2014;74:1833-44.
  30. Tuerff D, Sissung T, Figg WD. Cellular identity crisis: Antiandrogen resistance by lineage plasticity. Cancer Biol Ther 2017;18:841-2.
  31. Rybak AP, Tang D. SOX2 plays a critical role in EGFRmediated self-renewal of human prostate cancer stem-like cells. Cell Signal 2013;25:2734-42.
  32. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017;355:78-83.
  33. 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:e19059.
  34. 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;69:16-22.
  35. 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;1:582-91.
  36. Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol 2016;2:1441-9.
  37. 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;20:3198-210.
  38. Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, et al. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS One 2018;13:e0198389.
  39. Ferraldeschi R, Welti J, Powers MV, Yuan W, Smyth T, Seed G, et al. Second-generation HSP90 inhibitor onalespib blocks mRNA splicing of androgen receptor variant 7 in prostate cancer cells. Cancer Res 2016;76:2731-42.
  40. Jones D, Noble M, Wedge SR, Robson CN, Gaughan L. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer. Sci Rep 2017;7:40957.
  41. Beltran H, Oromendia C, Danila DC, Montgomery B, Hoimes C, Szmulewitz RZ, et al. A phase II trial of the aurora kinase a inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: efficacy and biomarkers. Clin Cancer Res 2018 Sep 19 [Epub].