Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Drug discovery in advanced prostate cancer: translating biology into therapy

Key Points

  • Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges.

  • Recent genetic and technological advances have provided insights into prostate cancer biology and enabled the identification of novel drug targets and potent molecularly targeted therapeutics for the disease.

  • Promising targets in CRPC include the androgen receptor and its variants, key signalling pathways such as phosphoinositide 3-kinase (PI3K)–AKT and WNT signalling, and DNA repair defects.

  • The therapeutic landscape of CRPC is evolving, with an increased focus on research into tumour heterogeneity, immuno-oncology, minimally invasive circulating tissue biomarkers, and modern clinical trial designs.

  • The use of state-of-the-art, high-throughput, genomic platforms enabling patient stratification will permit optimization of the development of current and future drugs for CRPC.

Abstract

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The cellular biology of prostate cancer.
Figure 2: CRPC treatment in the present and in the future.

References

  1. 1

    Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013).

    Article  Google Scholar 

  2. 2

    Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Prostate Cancer Trialists' Collaborative Group. Lancet 346, 265–269 (1995).

  3. 3

    Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl Med. 4, 127ps110 (2012).

    Google Scholar 

  5. 5

    Yap, T. A., Zivi, A., Omlin, A. & de Bono, J. S. The changing therapeutic landscape of castration-resistant prostate cancer. Nat. Rev. Clin. Oncol. 8, 597–610 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011). An important paper demonstrating the genomic complexity of prostate cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Kumar, A. et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc. Natl Acad. Sci. USA 108, 17087–17092 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012). An important paper describing the mutational landscape of CRPC.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Ozsolak, F. & Milos, P. M. RNA sequencing: advances, challenges and opportunities. Nat. Rev. Genet. 12, 87–98 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Sreekumar, A. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Tucker, T., Marra, M. & Friedman, J. M. Massively parallel sequencing: the next big thing in genetic medicine. Am. J. Hum. Genet. 85, 142–154 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Stratton, M. R. Exploring the genomes of cancer cells: progress and promise. Science 331, 1553–1558 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Mu, P. et al. TP53 and RB1 alterations promote reprogramming and antiandrogen resistance in advanced prostate cancer [abstract]. Cancer Res. 75 (Suppl.), LB-056 (2015).

    Google Scholar 

  16. 16

    Zhao, J., Zhang, Z., Liao, Y. & Du, W. Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. Am. J. Cancer Res. 4, 42–52 (2014).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015). An important study of integrative clinical genomics of advanced prostate cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Robbins, C. M. et al. Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res. 21, 47–55 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Fairley, J. A., Gilmour, K. & Walsh, K. Making the most of pathological specimens: molecular diagnosis in formalin-fixed, paraffin embedded tissue. Curr. Drug Targets 13, 1475–1487 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Holcomb, I. N. et al. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res. 68, 5599–5608 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Ryan, C. J. & Tindall, D. J. Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. J. Clin. Oncol. 29, 3651–3658 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01385293 (2015).

  24. 24

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01741753 (2016).

  25. 25

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01485861 (2015).

  26. 26

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01884285 (2016).

  27. 27

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01458067 (2016).

  28. 28

    Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Yap, T. et al. Final results of a translational phase l study assessing a QOD schedule of the potent AKT inhibitor MK-2206 incorporating predictive, pharmacodynamic (PD), and functional imaging biomarkers [abstract]. J. Clin. Oncol. 29 (Suppl.) 3001 (2011).

    Google Scholar 

  30. 30

    Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). An important study identifying TMPRSS2 and ETS genes in prostate cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Holzbeierlein, J. et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 164, 217–227 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Scher, H. I. & Sawyers, C. L. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J. Clin. Oncol. 23, 8253–8261 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Stanbrough, M. et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815–2825 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Yu, X. et al. Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Ann. NY Acad. Sci. 1061, 77–93 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Robinson, J. L. et al. Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype. Oncogene (2013).

    Google Scholar 

  36. 36

    Hornberg, E. et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 6, e19059 (2011).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Hu, R., Isaacs, W. B. & Luo, J. A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate 71, 1656–1667 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Antonarakis, E. S., Nakazawa, M. & Luo, J. Resistance to androgen-pathway drugs in prostate cancer. N. Engl. J. Med. 371, 2234 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Antonarakis, E. S. et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 1, 582–591 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41

    Onstenk, W. et al. Efficacy of cabazitaxel in castration-resistant prostate cancer is independent of the presence of AR-V7 in circulating tumor cells. Eur. Urol. 68, 939–945 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ravindranathan, P. et al. Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer. Nat. Commun. 4, 1923 (2013).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Crea, F. et al. Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer. Oncotarget 5, 764–774 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Du, Z. et al. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat. Struct. Mol. Biol. 20, 908–913 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Prensner, J. R. et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol. 15, 1469–1480 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Palanisamy, N. et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat. Med. 16, 793–798 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Ren, S. et al. RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res. 22, 806–821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Burkhardt, L. et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 73, 2795–2805 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Liu, W. et al. Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer. Oncogene 31, 3939–3948 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Xu, K. et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Fellmann, C. & Lowe, S. W. Stable RNA interference rules for silencing. Nat. Cell Biol. 16, 10–18 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yegnasubramanian, V. in State of the Science Report: Highlights from the 20th Annual PCF Scientific Retreat (Prostate Cancer Foundation, 2013).

    Google Scholar 

  53. 53

    Plass, C. et al. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet. 14, 765–780 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Duan, Z. et al. Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate via MLL histone methylase complex. Prostate 73, 455–466 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Asangani, I. A. et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278–282 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Gao, L. et al. Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. PloS ONE 8, e63563 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Attard, G., Ang, J. E., Olmos, D. & de Bono, J. S. Dissecting prostate carcinogenesis through ETS gene rearrangement studies: implications for anticancer drug development. J. Clin. Pathol. 61, 891–896 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Attard, G. et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27, 253–263 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Rhodes, D. R. et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1–6 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Tomlins, S. A. et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell 13, 519–528 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Rhodes, D. R. et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166–180 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Kaushik, A. K. et al. Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer. J. Proteome Res. 13, 1088–1100 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Belanger, A., Pelletier, G., Labrie, F., Barbier, O. & Chouinard, S. Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol. Metab. 14, 473–479 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Shafi, A. A., Yen, A. E. & Weigel, N. L. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol. Ther. 140, 223–238 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Ferraldeschi, R., Welti, J., Luo, J., Attard, G. & de Bono, J. S. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene 34, 1745–1757 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Dar, J. A. et al. N-terminal domain of the androgen receptor contains a region that can promote cytoplasmic localization. J. Steroid Biochem. Mol. Biol. 139, 16–24 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Suzuki, H. et al. Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate 29, 153–158 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Hara, T., Kouno, J., Nakamura, K., Kusaka, M. & Yamaoka, M. Possible role of adaptive mutation in resistance to antiandrogen in prostate cancer cells. Prostate 65, 268–275 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    van de Wijngaart, D. J. et al. Systematic structure–function analysis of androgen receptor Leu701 mutants explains the properties of the prostate cancer mutant L701H. J. Biol. Chem. 285, 5097–5105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Thompson, J., Saatcioglu, F., Janne, O. A. & Palvimo, J. J. Disrupted amino- and carboxyl-terminal interactions of the androgen receptor are linked to androgen insensitivity. Mol. Endocrinol. 15, 923–935 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Sack, J. S. et al. Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc. Natl Acad. Sci. USA 98, 4904–4909 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Haile, S. & Sadar, M. D. Androgen receptor and its splice variants in prostate cancer. Cell. Mol. Life Sci. 68, 3971–3981 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L. & Tindall, D. J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68, 5469–5477 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Li, Y. et al. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 73, 483–489 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Debes, J. D. & Tindall, D. J. Mechanisms of androgen-refractory prostate cancer. N. Engl. J. Med. 351, 1488–1490 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Mateo, J., Smith, A., Ong, M. & de Bono, J. S. Novel drugs targeting the androgen receptor pathway in prostate cancer. Cancer Metastasis Rev. 33, 567–579 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Lam, J. S., Leppert, J. T., Vemulapalli, S. N., Shvarts, O. & Belldegrun, A. S. Secondary hormonal therapy for advanced prostate cancer. J. Urol. 175, 27–34 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Clegg, N. J. et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 72, 1494–1503 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Ferraldeschi, R., Sharifi, N., Auchus, R. J. & Attard, G. Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin. Cancer Res. 19, 3353–3359 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Li, Z. et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Andersen, R. J. et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17, 535–546 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Myung, J. K. et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J. Clin. Invest. 123, 2948–2960 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Brand, L. J. et al. EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer. Oncotarget 6, 3811–3824 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Montgomery, R. B. 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. 33 (Suppl.), TPS5072 (2015).

    Google Scholar 

  87. 87

    Dalal, K. et al. Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. J. Biol. Chem. 289, 26417–26429 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Knapp, R. T. et al. BAG-1 diversely affects steroid receptor activity. Biochem. J. 441, 297–303 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Ferraldeschi, R. et al. In vitro and in vivo antitumor activity of the next generation HSP90 inhibitor, AT13387, in both hormone-sensitive and castration-resistant prostate cancer models. Cancer Res. 73 (Suppl.), 2433 (2013).

    Google Scholar 

  90. 90

    Solit, D. B., Scher, H. I. & Rosen, N. Hsp90 as a therapeutic target in prostate cancer. Semin. Oncol. 30, 709–716 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Solit, D. B. et al. 17-Allylamino-17- demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin. Cancer Res. 8, 986–993 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  92. 92

    Hieronymus, H. et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10, 321–330 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Ferraldeschi, R. et al. Second-generation HSP90 inhibitor onalespib blocks mRNA splicing of androgen receptor variant 7 in prostate cancer cells. Cancer Res. 76, 2731–2742 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Pacey, S. et al. A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin. Cancer Res. 17, 1561–1570 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Oh, W. K. et al. Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer. Urology 78, 626–630 (2011).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Iyer, G. et al. A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors. Cancer Chemother. Pharmacol. 69, 1089–1097 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Ferraldeschi, R. et al. A Phase 1/2 study of AT13387, a heat shock protein 90 (Hsp90) inhibitor in combination with abiraterone acetate (AA) and prednisone (P) in patients with castration-resistant prostate cancer (mCRPC) no longer responding to AA. Ann. Oncol. 25 (Suppl. 4), iv255–iv279 (2014).

    Google Scholar 

  98. 98

    Libertini, S. J. et al. Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res. 67, 9001–9005 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Yamashita, S. et al. ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia 14, 74–83 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    McClurg, U. L. & Robson, C. N. Deubiquitinating enzymes as oncotargets. Oncotarget 6, 9657–9668 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. 101

    McClurg, U. L., Summerscales, E. E., Harle, V. J., Gaughan, L. & Robson, C. N. Deubiquitinating enzyme Usp12 regulates the interaction between the androgen receptor and the Akt pathway. Oncotarget 5, 7081–7092 (2014).

    PubMed  PubMed Central  Google Scholar 

  102. 102

    Mostaghel, E. A. et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 67, 5033–5041 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Bohrer, L. R. et al. FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. Prostate 73, 1017–1027 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Dehm, S. M., Regan, K. M., Schmidt, L. J. & Tindall, D. J. Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion independent prostate cancer cells. Cancer Res. 67, 10067–10077 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Dehm, S. M. & Tindall, D. J. Alternatively spliced androgen receptor variants. Endocr. Relat. Cancer 18, R183–R196 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Reid, A. H. et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer 102, 678–684 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Carver, B. S. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Clegg, N. J. et al. MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors. PLoS ONE 6, e17449 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Schwartz, S. et al. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell 27, 109–122 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Rajan, P. et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur. Urol. 66, 32–39 (2013).

    PubMed  PubMed Central  Google Scholar 

  113. 113

    Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Waaler, J. et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 72, 2822–2832 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Riffell, J. L., Lord, C. J. & Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov. 11, 923–936 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Janku, F. et al. Phase I study of WNT974, a first-in-class Porcupine inhibitor, in advanced solid tumors. Mol. Cancer Ther. 14 (Suppl. 2), C45 (2015).

    Google Scholar 

  117. 117

    Beltran, H. DNA mismatch repair in prostate cancer. J. Clin. Oncol. 31, 1782–1784 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Ceccaldi, R. et al. A unique subset of epithelial ovarian cancers with platinum sensitivity and PARP inhibitor resistance. Cancer Res. 75, 628–634 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015). An important report showing the high response rate of patients with CRPC with DNA repair defects to the PARP inhibitor olaparib.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Schiewer, M. J. et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2, 1134–1149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 6 July 2016 [epub ahead of print].

  123. 123

    Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015). An excellent study of genomic markers of response to CTLA4 blockade.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015). An important paper demonstrating that MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Graff, J. N., Puri, S., Bifulco, C. B., Fox, B. A. & Beer, T. M. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer. Cancer Immunol. Res. 2, 399–403 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Hollenhorst, P. C., McIntosh, L. P. & Graves, B. J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu. Rev. Biochem. 80, 437–471 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Yu, J. et al. An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 17, 443–454 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Tomlins, S. A. et al. Role of the TMPRSS2–ERG gene fusion in prostate cancer. Neoplasia 10, 177–188 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Carver, B. S. et al. ETS rearrangements and prostate cancer initiation. Nature 457, E1; discussion E2–E3 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Zong, Y. et al. ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc. Natl Acad. Sci. USA 106, 12465–12470 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Yeh, J. E., Toniolo, P. A. & Frank, D. A. Targeting transcription factors: promising new strategies for cancer therapy. Curr. Opin. Oncol. 25, 652–658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Nhili, R. et al. Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines. Nucleic Acids Res. 41, 125–138 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Shao, L. et al. Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors. Clin. Cancer Res. 18, 6648–6657 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Vainio, P. et al. Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. Am. J. Pathol. 178, 525–536 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Vainio, P. et al. Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins. Oncotarget 2, 1176–1190 (2011).

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Iljin, K. et al. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res. 15, 6070–6078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Erkizan, H. V. et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat. Med. 15, 750–756 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Rahim, S. et al. YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. PLoS ONE 6, e19343 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Aytes, A. et al. ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proc. Natl Acad. Sci. USA 110, E3506–E3515 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Lotan, T. L. et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod. Pathol. 24, 820–828 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Mosquera, J. M. et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 15, 1–10 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Brockmann, M. et al. Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-Myc in childhood neuroblastoma. Cancer Cell 24, 75–89 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004). Phase III trial demonstrating survival benefit of docetaxel plus prednisolone.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011). Phase III trial showing survival benefit of abiraterone after chemotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2012). Phase III trial demonstrating survival benefit of abiraterone before chemotherapy.

    PubMed  PubMed Central  Google Scholar 

  147. 147

    Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). Phase III trial showing survival benefit of enzalutamide.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Beer, T. M. et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study. J. Clin. Oncol. 32, (Suppl. 4), LBA1 (2014).

    Google Scholar 

  149. 149

    de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010). Phase III trial showing survival benefit of cabazitaxel.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013). Positive phase III trial of radium-223.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010). Positive phase III trial of sipuleucel-T.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015). An important study showing that administration of docetaxel at the beginning of androgen-deprivation therapy results in longer overall survival.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    James, N. D. et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476). J. Clin. Oncol. 33, (Suppl.) 5001 (2015).

    Google Scholar 

  154. 154

    Masson, S. & Bahl, A. Metastatic castrate-resistant prostate cancer: dawn of a new age of management. BJU Int. 110, 1110–1114 (2012).

    PubMed  PubMed Central  Google Scholar 

  155. 155

    Lorente, D., Mateo, J., Perez-Lopez, R., de Bono, J. S. & Attard, G. Sequencing of agents in castration-resistant prostate cancer. Lancet Oncol. 16, e279–e292 (2015).

    PubMed  PubMed Central  Google Scholar 

  156. 156

    Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012). A seminal paper demonstrating intratumour heterogeneity and branched evolution using multiregion sequencing.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    McArdle, P. A., McMillan, D. C., Sattar, N., Wallace, A. M. & Underwood, M. A. The relationship between interleukin-6 and C-reactive protein in patients with benign and malignant prostate disease. Br. J. Cancer 91, 1755–1757 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Davidsson, S. et al. CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3+ regulatory T cells with respect to lethal prostate cancer. Mod. Pathol. 26, 448–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Ness, N. et al. Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer. Prostate 74, 1452–1461 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Gannon, P. O. et al. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J. Immunol. Methods 348, 9–17 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Tse, B. W. et al. From bench to bedside: immunotherapy for prostate cancer. Biomed. Res. Int. 2014, 981434 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Sheikh, N. A. et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol. Immunother. 62, 137–147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Small, E. J. et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 13, 1810–1815 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Slovin, S. F. et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann. Oncol. 24, 1813–1821 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Kwon, E. D. 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. 15, 700–712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Attard, G. et al. Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer. Br. J. Cancer 99, 314–320 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Attard, G. & de Bono, J. S. Prostate cancer: PSA as an intermediate end point in clinical trials. Nature Rev. Urol. 6, 473–475 (2009).

    Google Scholar 

  173. 173

    Kantoff, P. W. et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Attard, G. et al. Hormone-sensitive prostate cancer: a case of ETS gene fusion heterogeneity. J. Clin. Pathol. 62, 373–376 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Yap, T. A., Sandhu, S. K., Workman, P. & de Bono, J. S. Envisioning the future of early anticancer drug development. Nat. Rev. Cancer 10, 514–523 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Andre, F. et al. Prioritizing targets for precision cancer medicine. Ann. Oncol. 25, 2295–2303 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Logothetis, C. J. et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 13, 1210–1217 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Yap, T. A., Lorente, D., Omlin, A., Olmos, D. & de Bono, J. S. Circulating tumor cells: a multifunctional biomarker. Clin. Cancer Res. 20, 2553–2568 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Danila, D. C., Fleisher, M. & Scher, H. I. Circulating tumor cells as biomarkers in prostate cancer. Clin. Cancer Res. 17, 3903–3912 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Azad, A. A. et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin. Cancer Res. 21, 2315–2324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Carreira, S. et al. Tumor clone dynamics in lethal prostate cancer. Sci. Transl Med. 6, 254ra125 (2014).

    PubMed  PubMed Central  Google Scholar 

  182. 182

    Romanel, A. et al. Plasma AR and abiraterone-resistant prostate cancer. Sci. Transl Med. 7, 312re310 (2015).

    Google Scholar 

  183. 183

    Laxman, B. et al. A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. 68, 645–649 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Kharaziha, P. et al. Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel. Oncotarget 6, 21740–21754 (2015).

    PubMed  PubMed Central  Google Scholar 

  185. 185

    Duijvesz, D., Luider, T., Bangma, C. H. & Jenster, G. Exosomes as biomarker treasure chests for prostate cancer. Eur. Urol. 59, 823–831 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Attard, G. et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 69, 2912–2918 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Lawrence, M. G. et al. A preclinical xenograft model of prostate cancer using human tumors. Nat. Protoc. 8, 836–848 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).

    CAS  Google Scholar 

  190. 190

    Heitzer, E. et al. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med. 5, 30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Ross, R. W. et al. A whole-blood RNA transcript-based prognostic model in men with castration-resistant prostate cancer: a prospective study. Lancet Oncol. 13, 1105–1113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Olmos, D. et al. Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study. Lancet Oncol. 13, 1114–1124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193

    Miyamoto, D. T. et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349, 1351–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Rodon, J. et al. Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial. Ann. Oncol. 26, 1791–1798 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Smith, A. D., Roda, D. & Yap, T. A. Strategies for modern biomarker and drug development in oncology. J. Hematol. Oncol. 7, 70 (2014).

    PubMed  PubMed Central  Google Scholar 

  196. 196

    Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    de Bono, J. S. & Ashworth, A. Translating cancer research into targeted therapeutics. Nature 467, 543–549 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Shendure, J. & Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 26, 1135–1145 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Summerer, D. et al. Targeted high throughput sequencing of a cancer-related exome subset by specific sequence capture with a fully automated microarray platform. Genomics 95, 241–246 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Tayeh, M. K. et al. Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications. Genet. Med. 11, 232–240 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10, 57–63 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Koboldt, D. C., Steinberg, K. M., Larson, D. E., Wilson, R. K. & Mardis, E. R. The next-generation sequencing revolution and its impact on genomics. Cell 155, 27–38 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    De Lellis, L. et al. Analysis of extended genomic rearrangements in oncological research. Ann. Oncol. 18 (Suppl. 6), vi173–vi178 (2007).

    PubMed Central  PubMed  Google Scholar 

  205. 205

    Hurd, P. J. & Nelson, C. J. Advantages of next-generation sequencing versus the microarray in epigenetic research. Brief Funct. Genomic Proteomic 8, 174–183 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Bass, B. L. RNA editing by adenosine deaminases that act on RNA. Annu. Rev. Biochem. 71, 817–846 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Hansen, K. D., Brenner, S. E. & Dudoit, S. Biases in Illumina transcriptome sequencing caused by random hexamer priming. Nucleic Acids Res. 38, e131 (2010).

    PubMed  PubMed Central  Google Scholar 

  208. 208

    Kozarewa, I. et al. Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of (G+C)-biased genomes. Nat. Methods 6, 291–295 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    Dohm, J. C., Lottaz, C., Borodina, T. & Himmelbauer, H. Substantial biases in ultra-short read data sets from high-throughput DNA sequencing. Nucleic Acids Res. 36, e105 (2008).

    PubMed  PubMed Central  Google Scholar 

  210. 210

    Liu, D. & Graber, J. H. Quantitative comparison of EST libraries requires compensation for systematic biases in cDNA generation. BMC Bioinformat. 7, 77 (2006).

    CAS  Google Scholar 

  211. 211

    Ozsolak, F. et al. Direct RNA sequencing. Nature 461, 814–818 (2009).

    CAS  Google Scholar 

  212. 212

    Bulusu, K. C. et al. canSAR: updated cancer research and drug discovery knowledgebase. Nucleic Acids Res. 42, D1040–D1047 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Patel, M. N., Halling-Brown, M. D., Tym, J. E., Workman, P. & Al-Lazikani, B. Objective assessment of cancer genes for drug discovery. Nat. Rev. Drug Discov. 12, 35–50 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 214

    Coffey, D. S. & Isaacs, J. T. Prostate tumor biology and cell kinetics — theory. Urology 17, 40–53 (1981).

    CAS  PubMed Central  PubMed  Google Scholar 

  215. 215

    Sfanos, K. S. et al. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 69, 1694–1703 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Mercader, M. et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc. Natl Acad. Sci. USA 98, 14565–14570 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Quinn, D. I., Shore, N. D., Egawa, S., Gerritsen, W. R. & Fizazi, K. Immunotherapy for castration-resistant prostate cancer: progress and new paradigms. Urol. Oncol. 33, 245–260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

    Gerritsen, W. R. & Sharma, P. Current and emerging treatment options for castration-resistant prostate cancer: a focus on immunotherapy. J. Clin. Immunol. 32, 25–35 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 220

    Podrazil, M. et al. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer. Oncotarget 6, 18192–18205 (2015).

    PubMed  PubMed Central  Google Scholar 

  221. 221

    Sonpavde, G. et al. Results of a phase I/II clinical trial of BPX-101, a novel drug-activated dendritic cell (DC) vaccine for metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 29 (Suppl. 7), 132 (2011).

    Google Scholar 

  222. 222

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01322490 (2015).

  223. 223

    Noguchi, M. et al. A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer. Cancer Immunol. Immunother. 59, 1001–1009 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224

    Higano, C. et al. A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC) [abstract]. Genitourinary Cancers Symposium 2009 http://meetinglibrary.asco.org/content/20543-64 (2009).

    Google Scholar 

  225. 225

    Small, E. et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC) [abstract]. Genitourinary Cancers Symposium 2009 http://meetinglibrary.asco.org/content/20295-64 (2009).

    Google Scholar 

  226. 226

    Attard, G. et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 27, 3742–3748 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 227

    Attard, G., Reid, A. H., Dearnaley, D. & De Bono, J. S. New prostate cancer drug: prostate cancer's day in the sun. BMJ 337, a1249 (2008).

    PubMed  PubMed Central  Google Scholar 

  228. 228

    Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    CAS  Google Scholar 

  229. 229

    Kong, D. et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PloS ONE 7, e33729 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    Bishop, J. L. et al. PD-L1 is highly expressed in enzalutamide resistant prostate cancer. Oncotarget 6, 234–242 (2015).

    PubMed  PubMed Central  Google Scholar 

  231. 231

    Crane, C. A. et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 28, 306–312 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232

    Attard, G., Reid, A. H., Olmos, D. & de Bono, J. S. Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res. 69, 4937–4940 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Attard, G. et al. A novel, spontaneously immortalized, human prostate cancer cell line, Bob, offers a unique model for pre-clinical prostate cancer studies. Prostate 69, 1507–1520 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01251861 (2016).

  235. 235

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02121639 (2014).

  236. 236

    Ayhan, A., Ertunc, D., Tok, E. C. & Ayhan, A. Expression of the c-Met in advanced epithelial ovarian cancer and its prognostic significance. Int. J. Gynecol. Cancer 15, 618–623 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

    Reaper, P. M. et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat. Chem. Biol. 7, 428–430 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    Henriquez-Hernandez, L. A. et al. Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression. BMC Med. Genet. 15, 143 (2014).

    PubMed  PubMed Central  Google Scholar 

  239. 239

    Wang, S. et al. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc. Natl Acad. Sci. USA 111, 4251–4256 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240

    Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Sandhu, S. K. et al. Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of advanced germline BRCA2 mutant prostate cancer. Ann. Oncol. 24, 1416–1418 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01682772 (2014).

  243. 243

    Ateeq, B. et al. Therapeutic targeting of SPINK1-positive prostate cancer. Sci. Transl Med. 3, 72ra17 (2011).

    PubMed  PubMed Central  Google Scholar 

  244. 244

    Rodrigues, L. U. et al. Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res. 75, 1021–1034 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245

    Attard, G. et al. Prostate cancer. 387, 70–78 Lancet (2015).

    PubMed  PubMed Central  Google Scholar 

  246. 246

    Huang, S. et al. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene 31, 4164–4170 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247

    Bruxvoort, K. J. et al. Inactivation of Apc in the mouse prostate causes prostate carcinoma. Cancer Res. 67, 2490–2496 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. 248

    Wyce, A. et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4, 2419–2429 (2013).

    PubMed  PubMed Central  Google Scholar 

  249. 249

    Rathkopf, D. E. et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 31, 3525–3530 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01946204 (2016).

  251. 251

    Smith, M. R. et al. Final analysis of COMET-1: cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). J. Clin. Oncol. 33 (Suppl. 7), 139 (2015).

    Google Scholar 

  252. 252

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01574937 (2016).

  253. 253

    Chi, K. N. et al. Phase III SYNERGY trial: docetaxel +/− custirsen and overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and poor prognosis. J. Clin. Oncol. 33 (Suppl.), 5009 (2015).

    Google Scholar 

  254. 254

    Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  Google Scholar 

  255. 255

    Spisek, R. et al. Phase I/II clinical trials of dendritic cell-based immunotherapy in patients with the biochemical relapse of the prostate cancer. J. Clin. Oncol. 31 (Suppl.), e16002 (2013).

    Google Scholar 

  256. 256

    European Medicines Agency. EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-004735-32 (2012).

  257. 257

    Shore, N. D. et al. Phase III efficacy and safety trial of a new leuprolide acetate 3.75 mg depot formulation in prostate cancer patients. J. Clin. Oncol. 27 (Suppl.), e16152 (2009).

    Google Scholar 

  258. 258

    Dreicer, R. et al. 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). J. Clin. Oncol. 32 (Suppl. 4), 7 (2014).

    Google Scholar 

  259. 259

    Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932–20937 (2007).

    CAS  Google Scholar 

  260. 260

    Xu, F. et al. Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors. Cancer Gene Ther. 16, 723–730 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

    US National Library of Medicine. ClinicalTrials.govhttps://www.clinicaltrials.gov/ct2/show/NCT01436968 (2016).

  262. 262

    Araujo, J. C. et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 14, 1307–1316 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    Pili, R. et al. Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J. Clin. Oncol. 29, 4022–4028 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01234311 (2015).

  265. 265

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01360840 (2015).

  266. 266

    Festuccia, C. et al. Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors. Prostate 70, 1340–1349 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  267. 267

    Bullrich, F. et al. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res. 59, 24–27 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  268. 268

    Tagawa, S. T. et al. Phase II study of lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin. Cancer Res. 19, 5182–5191 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. 269

    Burgess, T. et al. Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res. 66, 1721–1729 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. 270

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01812746 (2016).

  271. 271

    Yu, E. Y. et al. The effect of low-dose GTx-758 on free testerone levels in men with metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 32 (Suppl. 4), 60 (2014).

    Google Scholar 

  272. 272

    de Souza, P. L., Castillo, M. & Myers, C. E. Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine. Br. J. Cancer 75, 1593–1600 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. 273

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT00417274 (2013).

  274. 274

    Chi, K. N. et al. A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a. Ann. Oncol. 23, 53–58 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. 275

    Denmeade, S. R. et al. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Sci. Transl Med. 4, 140ra186 (2012).

    Google Scholar 

  276. 276

    Carser, J. E. et al. BRCA1 protein expression as a predictor of outcome following chemotherapy in sporadic epithelial ovarian cancer (EOC). J. Clin. Oncol. 27 (Suppl.), 5527 (2009).

    Google Scholar 

  277. 277

    Higano, C. S. et al. Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 113, 975–984 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278

    Kabbinavar, F. F. et al. An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC). J. Clin. Oncol. 32 (Suppl.), 169 (2014).

    Google Scholar 

  279. 279

    Hong, D. S. et al. A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer. Clin. Cancer Res. 17, 6582–6591 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. 280

    Liu, G., Chen, Y. H., Dipaola, R., Carducci, M. & Wilding, G. Phase II trial of weekly ixabepilone in men with metastatic castrate-resistant prostate cancer (E3803): a trial of the Eastern Cooperative Oncology Group. Clin. Genitourin Cancer 10, 99–105 (2012).

    PubMed  PubMed Central  Google Scholar 

  281. 281

    Antonarakis, E. S. et al. A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemother. Pharmacol. 71, 883–892 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  282. 282

    North, S. A., Graham, K., Bodnar, D. & Venner, P. A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy. J. Urol. 176, 91–95 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. 283

    Chiorean, E. G. et al. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 73, 595–604 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  284. 284

    Chalmers, A. J. Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target. Clin. Oncol. 16, 29–39 (2004).

    CAS  Google Scholar 

  285. 285

    Fizazi, K. et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 15, 975–985 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. 286

    Brose, M. S. et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J. Natl Cancer Inst. 94, 1365–1372 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. 287

    Hotte, S. J. et al. Phase I trial of OGX-427, a 2′methoxyethyl antisense oligonucleotide (ASO), against heat shock protein 27 (Hsp27): final results. J. Clin. Oncol. 28 (Suppl.), 3077 (2010).

    Google Scholar 

  288. 288

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. 289

    Hawkins, R. E. et al. Safety and tolerability of PCK3145, a synthetic peptide derived from prostate secretory protein 94 (PSP94) in metastatic hormone-refractory prostate cancer. Clin. Prostate Cancer 4, 91–99 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  290. 290

    Meulenbeld, H. J. et al. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int. 111, 44–52 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291

    Anthony, S. P. et al. Pharmacodynamic activity demonstrated in phase I for PLX3397, a selective inhibitor of FMS and Kit. J. Clin. Oncol. 29 (Suppl.), 3093 (2011).

    Google Scholar 

  292. 292

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01499043 (2015).

  293. 293

    Petrylak, D. P. et al. Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): a phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. J. Clin. Oncol. 31 (Suppl. 6), 119 (2013).

    Google Scholar 

  294. 294

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01695044 (2015).

  295. 295

    Spratlin, J. L. et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J. Clin. Oncol. 28, 780–787 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK. Support is also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Johann S. de Bono.

Ethics declarations

Competing interests

All authors are current or former employees of The Institute of Cancer Research, London, UK, which has a commercial interest in the development of abiraterone acetate and phosphoinositide 3-kinase (PI3K) inhibitors, including pictilisib, and operates a rewards-to-discoverers scheme. T.A.Y. has received research funding from AstraZeneca and Vertex Pharmaceuticals; is or was a consultant or advisory board member for Pfizer and Merck Serono; and has received travel support from Bristol-Myers Squibb, Janssen and Merck. R.F. is an employee of Astex Pharmaceuticals. P.W. has received research funding from Astellas Pharma and Piramed Pharma, has ownership interest in Chroma Therapeutics and previously Piramed Pharma, and is or was a consultant or advisory board member for Chroma Therapeutics, Nextech Invest, NuEvolution and Piramed Pharma. J.S.d.B. has received consulting fees from Ortho Biotech Oncology Research and Development; consulting fees and travel support from Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen and Takeda; and grant support from AstraZeneca and Genentech.

Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Supplementary information (XLSX 31 kb)

Glossary

Oncogenome

The collection of cancer-associated genes, epigenetics and transcripts.

Massively parallel sequencing

A method of high-throughput DNA sequencing using multiple sequencing in parallel via spatially separated, clonally amplified DNA templates.

Sequencing depth

The number of times a nucleotide is read during DNA sequencing. Deep sequencing requires a high number of reads.

Base-calling

The identification of a particular base in a strand of nucleic acids.

Sequence coverage

The average number of reads representing a given nucleotide in a reconstructed sequence.

Actionable targets

Specific genomic events that potentially have important diagnostic, prognostic or therapeutic implications in subsets of patients with cancer and for specific therapies.

Comparative genomic hybridization array

(aCGH). An analysis of copy number variation relative to the ploidy level of a set of genes in a test sample.

Fluorescent in situ hybridization

(FISH). A technique using fluorescent nucleic acid probes to highlight only regions of the nucleic acid with a high degree of base sequence complementarity.

DNA methyltransferase

An enzyme that catalyses the transfer of a methyl group to DNA (that is, a type of epigenetic modification).

Microsatellite

Di-, tri- or tetranucleotide tandem repeats in DNA sequences.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yap, T., Smith, A., Ferraldeschi, R. et al. Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discov 15, 699–718 (2016). https://doi.org/10.1038/nrd.2016.120

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing