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A new era in prostate cancer therapy: new targets and novel therapeutics

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Abstract

The results of two phase III trials demonstrating a significant prolongation of survival with docetaxel-based chemotherapy has fueled interest in expanding therapeutic development in prostate cancer. This coupled with improved understanding of the mechanisms responsible for prostate cancer development and progression has lead to discovery of several biologic targets that can be exploited using novel therapeutics in what has been referred to as the era of “targeted therapy.” Several of these therapies have shown promise either as single agents or in combination with proven chemotherapeutic agents. This review focuses upon some of the more promising targeted therapies under investigation for the treatment of hormone refractory prostate cancer and highlights some of challenges faced in therapeutic development.

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References

  1. Tannock IF, de Wit R, Berry WR et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512

    Article  PubMed  CAS  Google Scholar 

  2. Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520

    Article  PubMed  CAS  Google Scholar 

  3. Shah RB, Mehra R, Chinnaiyan AM et al (2004) Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 64:9209–9216

    Article  PubMed  CAS  Google Scholar 

  4. Nelson JB, Hedican SP, George DJ et al (1995) Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1:944–949

    Article  PubMed  CAS  Google Scholar 

  5. Yin JJ, Mohammad KS, Kakonen SM et al (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci U S A 100:10954–10959

    Article  PubMed  CAS  Google Scholar 

  6. Pirtskhalaishvili G, Nelson JB (2000) Endothelium-derived factors as paracrine mediators of prostate cancer progression. Prostate 44:77–87

    Article  PubMed  CAS  Google Scholar 

  7. Thakkar SG, Choueiri TK, Garcia JA (2006) Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep 8:108–113

    Article  PubMed  CAS  Google Scholar 

  8. Carducci MA, Jimeno A (2006) Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res 12:6296s–6300s

    Article  PubMed  CAS  Google Scholar 

  9. Carducci MA, Padley RJ, Breul J et al (2003) Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 21:679–689

    Article  PubMed  CAS  Google Scholar 

  10. Vogelzang N, Nelson J, Schulman C et al (2005) Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer. J Clin Oncol 23:4563

    Google Scholar 

  11. Lipton A, Sleep DJ, Hulting SM et al (2004) Benefit of atrasentan in men with hormone refractory prostate cancer metastatic to bone. J Clin Oncol 22:4687

    Article  Google Scholar 

  12. Sleep DJ, Nelson JB, Petrylak DP et al (2006) Clinical benefit of atrasentan for men with metastatic hormone-refractory prostate cancer metastatic to bone. J Clin Oncol 24:4630

    Google Scholar 

  13. Banerjee S, Hussain M, Wang Z et al (2007) In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. Cancer Res 67:3818–3826

    Article  PubMed  CAS  Google Scholar 

  14. Morris CD, Rose A, Curwen J et al (2005) Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer 92:2148–2152

    Article  PubMed  CAS  Google Scholar 

  15. James ND, Borre M, Zonnenberg B et al (2007) ZD4054, a potent, specific endothelin A receptor antagonist, improves overall survival in pain-free or mildly symptomatic patients with hormone-resistant prostate cancer (HRPC) and bone metastases. Eur J Cancer Supplements 5:abstract 3LB

  16. Pidgeon GP, Tang K, Cai YL et al (2003) Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression. Cancer Res 63:4258–4267

    PubMed  CAS  Google Scholar 

  17. Brooks PC, Montgomery AM, Rosenfeld M et al (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164

    Article  PubMed  CAS  Google Scholar 

  18. Teitelbaum SL (2006) Osteoclasts and integrins. Ann N Y Acad Sci 1068:95–99

    Article  PubMed  CAS  Google Scholar 

  19. Dresner-Pollak R, Rosenblatt M (1994) Blockade of osteoclast-mediated bone resorption through occupancy of the integrin receptor: a potential approach to the therapy of osteoporosis. J Cell Biochem 56:323–330

    Article  PubMed  CAS  Google Scholar 

  20. Nemeth JA, Cher ML, Zhou Z et al (2003) Inhibition of alpha(v)beta3 integrin reduces angiogenesis, bone turnover, and tumor cell proliferation in experimental prostate cancer bone metastases. Clin Exp Metastasis 20:413–420

    Article  PubMed  CAS  Google Scholar 

  21. Duong LT, Lakkakorpi P, Nakamura I, Rodan GA (2000) Integrins and signaling in osteoclast function. Matrix Biol 19:97–105

    Article  PubMed  CAS  Google Scholar 

  22. Beekman KW, Colevas AD, Cooney K et al (2006) Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design. Clin Genitourin Cancer 4:299–302

    Article  PubMed  CAS  Google Scholar 

  23. Bradley DA, Dunn R, Ryan C et al (2007) EMD121974 (NSC 707544, cilengitide) in asymptomatic metastatic androgen independent prostate cancer (AIPCa) patients (pts): a randomized trial by the Prostate Cancer Clinical Trials Consortium (NCI 6372). J Clin Oncol 25:abstract 5137

    Google Scholar 

  24. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  PubMed  CAS  Google Scholar 

  25. Jimenez JA, Kao C, Raikwar S, Gardner TA (2006) Current status of anti-angiogenesis therapy for prostate cancer. Urol Oncol 24:260–268

    PubMed  CAS  Google Scholar 

  26. Bok RA, Halabi S, Fei DT et al (2001) Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study. Cancer Res 61:2533–2536

    PubMed  CAS  Google Scholar 

  27. Weidner N, Carroll PR, Flax J et al (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409

    PubMed  CAS  Google Scholar 

  28. Shariat SF, Anwuri VA, Lamb DJ et al (2004) Association of preoperative plasma levels of vascular endothelial growth factor and soluble vascular cell adhesion molecule-1 with lymph node status and biochemical progression after radical prostatectomy. J Clin Oncol 22:1655–1663

    Article  PubMed  CAS  Google Scholar 

  29. Borre M, Nerstrom B, Overgaard J (2000) Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res 6:1882–1890

    PubMed  CAS  Google Scholar 

  30. Kohli M, Kaushal V, Spencer HJ, Mehta P (2003) Prospective study of circulating angiogenic markers in prostate-specific antigen (PSA)-stable and PSA-progressive hormone-sensitive advanced prostate cancer. Urology 61:765–769

    Article  PubMed  CAS  Google Scholar 

  31. Retter AS, Figg WD, Dahut WL (2003) The combination of antiangiogenic and cytotoxic agents in the treatment of prostate cancer. Clin Prostate Cancer 2:153–159

    PubMed  CAS  Google Scholar 

  32. Dahut WL, Gulley JL, Arlen PM et al (2004) Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 22:2532–2539

    Article  PubMed  CAS  Google Scholar 

  33. Retter AS, Ando Y, Price DK et al (2005) Follow-up analysis of a randomized phase II study of docetaxel (D) and thalidomide (T) in androgen-independent prostate cancer (AIPC): updated survival data and stratification by CYP2C19 mutation status. Prostate Cancer Symposium 2005: abstract 265

  34. Reese D, Harris K, Corry M et al (2001) A phase II trial of humanized anti-vascular endothelial growth factor antibody for the treatment of androgen-independent prostate cancer. Prostate J 3:65–70

    Article  Google Scholar 

  35. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  36. Picus J, Halabi S, Rini B et al (2003) The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006. Proc Am Soc Clin Oncol 22:abstract 1578

    Google Scholar 

  37. Ryan CJ, Lin AM, Small EJ (2006) Angiogenesis inhibition plus chemotherapy for metastatic hormone refractory prostate cancer: history and rationale. Urol Oncol 24:250–253

    PubMed  CAS  Google Scholar 

  38. Verheul HM, Hammers H, van Erp K et al (2007) Vascular endothelial growth factor Trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res 13:4201–4208

    Article  PubMed  CAS  Google Scholar 

  39. Krajewska M, Krajewski S, Epstein JI et al (1996) Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol 1996 148:1567–1576

    CAS  Google Scholar 

  40. Raffo AJ, Perlman H, Chen MW et al (1995) Overexpression of Bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 55:4438–4445

    PubMed  CAS  Google Scholar 

  41. McConkey DJ, Greene G, Pettaway CA (1996) Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line. Cancer Res 56:5594–5599

    PubMed  CAS  Google Scholar 

  42. Catz SD, Johnson JL (2003) BCL-2 in prostate cancer: a minireview. Apoptosis 8:29–37

    Article  PubMed  CAS  Google Scholar 

  43. Tang DG, Porter AT (1997) Target to apoptosis: a hopeful weapon for prostate cancer. Prostate 32:284–293

    Article  PubMed  CAS  Google Scholar 

  44. Shaffer DR, Scher HI (2003) Prostate cancer: a dynamic illness with shifting targets. Lancet Oncol 4:407–414

    Article  PubMed  Google Scholar 

  45. Chaudhary KS, Abel PD, Stamp GW, Lalani E (2001) Differential expression of cell death regulators in response to thapsigargin and adriamycin in Bcl-2 transfected DU145 prostatic cancer cells. J Pathol 193:522–529

    Article  PubMed  CAS  Google Scholar 

  46. Baltogiannis D, Charalabopoulos K, Giannakopoulos X et al (2005) Combined use of antisense oligonucleotides and chemotherapeutics in the treatment of refractory prostate cancer. Exp Oncol 27:91–93

    PubMed  CAS  Google Scholar 

  47. Tolcher AW, Chi K, Kuhn J et al (2005) A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 11:3854–3861

    Article  PubMed  CAS  Google Scholar 

  48. Sternberg CN, Dumez H, Van Poppel H et al (2007) Multicenter randomized EORTC trial 30021 of docetaxel + oblimersen and docetaxel in patients (pts) with hormone refractory prostate cancer (HRPC). Proceedings 2007 Prostate Cancer Symposium: abstract 144

  49. Beer TM (2005) ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere. BJU Int 96:508–513

    Article  PubMed  CAS  Google Scholar 

  50. Beer TM, Eilers KM, Garzotto M et al (2003) Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 21:123–128

    Article  PubMed  CAS  Google Scholar 

  51. Beer TM, Ryan CW, Venner PM et al (2007) Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 25:669–674

    Article  PubMed  CAS  Google Scholar 

  52. Hudes G, Einhorn L, Ross E et al (1999) Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 17:3160–3166

    PubMed  CAS  Google Scholar 

  53. Hussain M, Tangen CM, Lara PN Jr. et al (2005) Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: a Southwest Oncology Group trial S0111. J Clin Oncol 23:8724–8729

    Article  PubMed  Google Scholar 

  54. Galsky MD, Small EJ, Oh WK et al (2005) Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 23:1439–1446

    Article  PubMed  CAS  Google Scholar 

  55. Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). J Biol Chem 272:2534–2541

    Article  PubMed  CAS  Google Scholar 

  56. Nettles JH, Li H, Cornett B et al (2004) The binding mode of epothilone A on alpha, beta-tubulin by electron crystallography. Science 305:866–869

    Article  PubMed  CAS  Google Scholar 

  57. Rosenberg JE, Weinberg VK, Kelly WK et al (2007) Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients: randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 110:556–563

    Article  PubMed  CAS  Google Scholar 

  58. Sternberg CN, Whelan P, Hetherington J et al (2005) Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer. Oncology 68:2–9

    Article  PubMed  CAS  Google Scholar 

  59. Sternberg CN, Petrylak D, Witjes F et al (2007) Satraplatin (S) demonstrates significant clinical benefits for the treatment of patients with HRPC: results of a randomized phase III trial. J Clin Oncol 25:abstract 5019

    Google Scholar 

  60. Pienta KJ, Bradley D (2006) Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 12:1665–1671

    Article  PubMed  CAS  Google Scholar 

  61. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  PubMed  CAS  Google Scholar 

  62. Solit DB, Scher HI, Rosen N (2003) Hsp90 as a therapeutic target in prostate cancer. Semin Oncol 30:709–716

    Article  PubMed  CAS  Google Scholar 

  63. Chen L, Meng S, Wang H et al (2005) Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther 4:1311–1319

    Article  PubMed  CAS  Google Scholar 

  64. Halkidou K, Gaughan L, Cook S et al (2004) Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59:177–189

    Article  PubMed  CAS  Google Scholar 

  65. Butler LM, Agus DB, Scher HI et al (2000) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60:5165–5170

    PubMed  CAS  Google Scholar 

  66. Kelly WK, O'Connor OA, Krug LM et al (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923–3931

    Article  PubMed  CAS  Google Scholar 

  67. Kelly WK, Richon VM, O'Connor O et al (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578–3588

    PubMed  CAS  Google Scholar 

  68. Beekman KW, Fleming MT, Scher HI et al (2005) Second-line chemotherapy for prostate cancer: patient characteristics and survival. Clin Prostate Cancer 4:86–90

    PubMed  CAS  Google Scholar 

  69. Hussain M, Dunn R, Rathkopf D et al (2007) Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): a phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862). J Clin Oncol 25: abstract 5132

    Google Scholar 

  70. Solit DB, Zheng FF, Drobnjak M et al (2002) 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

    PubMed  CAS  Google Scholar 

  71. Banerji U, O'Donnell A, Scurr M et al (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23:4152–4161

    Article  PubMed  CAS  Google Scholar 

  72. Ramanathan RK, Trump DL, Eiseman JL et al (2005) Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 11:3385–3391

    Article  PubMed  CAS  Google Scholar 

  73. Grem JL, Morrison G, Guo XD et al (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23:1885–1893

    Article  PubMed  CAS  Google Scholar 

  74. Goetz MP, Toft D, Reid J et al (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087

    Article  PubMed  CAS  Google Scholar 

  75. Majumder PK, Sellers WR (2005) Akt-regulated pathways in prostate cancer. Oncogene 24:7465–7474

    Article  PubMed  CAS  Google Scholar 

  76. Bandyopadhyay S, Pai SK, Hirota S et al (2004) PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res 64:7655–7660

    Article  PubMed  CAS  Google Scholar 

  77. Dong JT (2006) Prevalent mutations in prostate cancer. J Cell Biochem 97:433–447

    Article  PubMed  CAS  Google Scholar 

  78. Dreher T, Zentgraf H, Abel U et al (2004) Reduction of PTEN and p27kip1 expression correlates with tumor grade in prostate cancer. Analysis in radical prostatectomy specimens and needle biopsies. Virchows Arch 444:509–517

    Article  PubMed  Google Scholar 

  79. Fenic I, Franke F, Failing K et al (2004) Expression of PTEN in malignant and non-malignant human prostate tissues: comparison with p27 protein expression. J Pathol 203:559–566

    Article  PubMed  CAS  Google Scholar 

  80. Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1:34–45

    Article  PubMed  CAS  Google Scholar 

  81. Nan B, Snabboon T, Unni E et al (2003) The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. J Mol Endocrinol 31:169–183

    Article  PubMed  CAS  Google Scholar 

  82. Ghosh PM, Malik S, Bedolla R, Kreisberg JI (2003) Akt in prostate cancer: possible role in androgen-independence. Curr Drug Metab 4:487–496

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

D.A. Bradley is supported by NIH grant T32CA009357.

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No funds were received in support of this study.

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Correspondence to Cora N. Sternberg.

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Bradley, D.A., Hussain, M. & Sternberg, C.N. A new era in prostate cancer therapy: new targets and novel therapeutics. Targ Oncol 3, 31–39 (2008). https://doi.org/10.1007/s11523-007-0067-0

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