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山东大学学报（医学版） ›› 2015, Vol. 53 ›› Issue (9): 1-7.doi: 10.6040/j.issn.1671-7554.2.2015.002

• 前沿进展 •    下一篇

去势抵抗性前列腺癌的发生发展机制及药物治疗新进展

韩博1,2, 戚美1, 谭薇薇1, 杨木易1   

  1. 1. 山东大学医学院病理学教研室, 山东 济南 250012;
    2. 山东大学齐鲁医院病理科, 山东 济南 250012
  • 收稿日期:2015-05-25 出版日期:2015-09-10 发布日期:2015-09-10
  • 通讯作者: 韩博。E-mail:boh@sdu.edu.cn E-mail:boh@sdu.edu.cn
  • 基金资助:
    国家自然科学基金(81472417,81171951)

Castration-resistant prostate cancer: current understanding of mechanisms and emerging novel agents

HAN Bo1,2, QI Mei1, TAN Weiwei1, YANG Muyi1   

  1. 1. Department of Pathology, School of Medicine, Jinan 250012, Shandong, China;
    2. Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Received:2015-05-25 Online:2015-09-10 Published:2015-09-10
  • Contact: 韩博。E-mail:boh@sdu.edu.cn E-mail:boh@sdu.edu.cn

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摘要： 去势抵抗性前列腺癌(CRPC)患者预后极差。CRPC的发生和进展机制极为复杂,迄今尚未被完全阐明,因此治疗策略的选择仍是临床上极具挑战性的问题。近年来,治疗CRPC的新药不断涌现,包括雄激素合成抑制药物(阿比特龙)、雄激素受体(AR)抑制药物(恩杂鲁胺)、免疫治疗剂(sipuleucel-T)、放射剂(镭-223)和化疗药物(卡巴他赛)等。因而,针对CRPC的治疗有了更多选择,系统治疗亦发生了很大变化。简要综述近年来人们对CRPC发生发展机制的最新理解和最有前途的药物在CRPC治疗中获得的新进展。

关键词: 前列腺肿瘤, 镭-223, 药物治疗, 雄激素受体, Sipuleucel-T, 去势抵抗性, 恩杂鲁胺, 阿比特龙, 卡巴他赛

Abstract: Castration-resistant prostate cancer (CRPC) has an extremely poor prognosis and remains a significant clinical challenge as the underlying mechanisms are largely unknown. Recently, a broad range of novel therapeutic drugs has emerged for CRPC treatment, including androgen synthesis inhibitors (abiraterone), androgen receptor (AR) inhibitors (enzalutamide), immunotherapy (sipuleucel-T), radiopharmaceuticals (Radium-223) and chemotherapeutic agents(cabazitaxel). Therefore, clinical urologists have more choices for the treatment of CRPC patients and the strategies of the systematic therapy have undergone great changes. In this review, we briefly overviewed the current molecular understanding of CRPC and highlighted the recently approved and emerging therapeutics for patients with CRPC.

Key words: Castration-resistant, Cabazitaxel, Abiraterone, Radium-223, Androgen receptor, Sipuleucel-T, Prostatitic neoplasms, Enzalutamide, Drug treatment

中图分类号: 

  • R737.1
[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1):5-29.
[2] 叶定伟. 前列腺癌的流行病学和中国的发病趋势[J]. 中华外科杂志, 2006, 44(6):362-364.
[3] Zong Y, Goldstein AS. Adaptation or selection-mechanisms of castration-resistant prostate cancer[J]. Nat Rev Urol, 2013, 10(2):90-98.
[4] Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer[J]. Clin Cancer Res, 2006, 12(6):1665-1671.
[5] Mitsiades N. A road map to comprehensive androgen receptor axis targeting for castration-resistant prostate cancer[J]. Cancer Res, 2013, 73(15):4599-4605.
[6] Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges[J]. Genes Dev, 2010, 24(18):1967-2000.
[7] 李曾,廖洪. 去势抵抗性前列腺癌分子信号通路的研究新进展[J]. 肿瘤, 2014, 34(10):969-974. LI Zeng, LIAO Hong. New progress in the molecular signaling pathway of castration-resistant prostate cancer[J]. Tumor, 2014, 34(10):969-974.
[8] Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663[J]. J Clin Oncol, 2003, 21(14):2673-2678.
[9] Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer[J]. N Engl J Med, 1995, 332(21):1393-1398.
[10] Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer[J]. Cancer Cell, 2010, 18(1):11-22.
[11] Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer[J]. Nat Genet, 2012, 44(6):685-689.
[12] Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor[J]. Proc Natl Acad Sci U S A, 2010, 107(39):16759-16765.
[13] Hornberg E, Ylitalo EB, Crnalic S, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival[J]. PLoS One, 2011, 6(4):e19059. doi: 10.1371/journal.pone.0019059.
[14] Wang L, Song G, Chang X, et al. The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway[J]. Oncogene, 2014 Dec 15. doi: 10.1038/onc.2014.401. [Epub ahead of print]
[15] Logothetis CJ, Gallick GE, Maity SN, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer[J]. Cancer Discov, 2013, 3(8):849-861.
[16] Ueda T, Mawji NR, Bruchovsky N, et al. Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells[J]. J Biol Chem, 2002, 277(41):38087-38094.
[17] Mellinghoff IK, Vivanco I, Kwon A, et al. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability[J]. Cancer Cell, 2004, 6(5):517-527.
[18] van Bokhoven A, Varella-Garcia M, Korch C, et al. Molecular characterization of human prostate carcinoma cell lines[J]. Prostate, 2003, 57(3):205-225.
[19] Mulholland DJ, Tran LM, Li Y, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth[J]. Cancer Cell, 2011, 19(6):792-804.
[20] Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells[J]. Cancer Res, 2005, 65(23):10946-10951.
[21] Zhu P, Baek SH, Bourk EM, et al. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway[J]. Cell, 2006, 124(3):615-629.
[22] Luo JL, Tan W, Ricono JM, et al. Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin[J]. Nature, 2007, 446(7136):690-694.
[23] Bedoya DJ, Mitsiades N. Abiraterone acetate, a first-in-class CYP17 inhibitor, establishes a new treatment paradigm in castration-resistant prostate cancer[J]. Expert Rev Anticancer Ther, 2012, 12(1):1-3.
[24] Gelmann EP. Molecular biology of the androgen receptor[J]. J Clin Oncol, 2002, 20(13):3001-3015.
[25] Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583)[J]. J Clin Oncol, 2004, 22(6):1025-1033.
[26] 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[J]. Lancet Oncol, 2012, 13(10):983-992.
[27] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy[J]. N Engl J Med, 2013, 368(2):138-148.
[28] Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer[J]. Cancer Res, 2009, 69(7):2912-2918.
[29] Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer[J]. Science, 2009, 324(5928):787-790.
[30] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy[J]. N Engl J Med, 2012, 367(13):1187-1197.
[31] Beer. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study[J]. Clin Adv Hematol Oncol, 2014, 12(4 Suppl 11):3-4.
[32] Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study[J]. Lancet, 2010, 375(9724):1437-1446.
[33] Jilani A, George E, Adler AI. NICE guidance on cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen[J]. Lancet Oncol, 2012, 13(6):573-574.
[34] Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer[J]. N Engl J Med, 2014, 371(11):1028-1038.
[35] Thomas C, Lamoureux F, Crafter C, et al. Synergistic targeting of PI3K/AKT pathway and androgen receptor axis significantly delays castration-resistant prostate cancer progression in vivo[J]. Mol Cancer Ther, 2013, 12(11):2342-2355.
[36] Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide)[J]. Cancer Discov, 2013, 3(9):1030-1043.
[37] Di Lorenzo G, Buonerba C, Autorino R, et al. Castration-resistant prostate cancer: current and emerging treatment strategies[J]. Drugs, 2010, 70(8):983-1000.
[38] Shore ND, Mantz CA, Dosoretz DE, et al. Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer[J]. Cancer Control, 2013, 20(1):7-16.
[39] Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer[J]. N Engl J Med, 2010, 363(5):411-422.
[40] Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge(R)) for castration-resistant prostate cancer[J]. BJU Int, 2012, 110(2 Pt 2):99-104.
[41] Di Lorenzo G, Buonerba C, Kantoff PW. Immunotherapy for the treatment of prostate cancer[J]. Nat Rev Clin Oncol, 2011, 8(9):551-561.
[42] Goyal J, Antonarakis ES. Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases[J]. Cancer Lett, 2012, 323(2):135-146.
[43] Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer[J]. N Engl J Med, 2013, 369(3):213-223.
[44] Morris M, Hammers H, Sweeney C, et al. Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (Crpc): a phase I Prostate Cancer Clinical Trials Consortium Study[EB/OL]. [2015-05-25]. J Clin Oncol 31, 2013 (Suppl; abstr 5021). http://meetinglibrary.asco.org/content/115274-132.
[45] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer[J]. N Engl J Med, 2004, 351(15):1502-1512.
[46] de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial[J]. Lancet, 2010, 376(9747):1147-1154.
[47] Antonarakis E, Giannakakou P, Kirby B, et al. Taxy-nergy (NCT01718353): a randomized phase II trial examining an early switch from first-line docetaxel to cabazitaxel, or cabazitaxel to docetaxel, in men with metastatic castration-resistant prostate cancer (MCRPC)[EB/OL]. [2015-05-25]. J Clin Oncol 31, 2013 (Suppl; abstr TPS5100). http://meetinglibrary.asco.org/content/113670-132.
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