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Novel bone-targeting agents in prostate cancer

Abstract

Prostate cancer (PC) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death among American men. Bone is by far the most common site for metastasis. The median survival of patients from the development of bone metastases is 3 years. During this period, patients are at increased risk of skeletal-related events (SREs) including: intractable bone pain, pathological fractures and spinal-cord compression. Several novel bone-targeted agents including bisphosphonates, receptor activator of nuclear factor κB (RANK) ligand monoclonal antibodies, endothelin receptor antagonists, bone-seeking radioisotopes, selective estrogen receptor (ER) modulators and tyrosine kinase inhibitors are now available and under evaluation in clinical trials in PC patients with bone metastases. This review article will provide an overview of the multiple emerging novel bone-targeted therapies in PC.

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References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

    Article  Google Scholar 

  2. Coxon JP, Oades GM, Colston KW, Kirby RS . Advances in the use of bisphosphonates in the prostate cancer setting. Prostate Cancer Prostatic Dis 2004; 7: 99–104.

    Article  CAS  Google Scholar 

  3. Nemoto R, Nakamura I, Nishijima Y, Shiobara K, Shimizu M, Takehara T et al. Serum pyridinoline crosslinks as markers of tumour-induced bone resorption. Br J Urol 1997; 80: 274–280.

    Article  CAS  Google Scholar 

  4. Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E . Correlation between bone metabolic markers and bone scan in prostatic cancer. J Urol 1997; 157: 539–543.

    Article  CAS  Google Scholar 

  5. Roodman GD . Biology of osteoclast activation in cancer. J Clin Oncol 2001; 19: 3562–3571.

    Article  CAS  Google Scholar 

  6. Oefelein MG, Resnick MI . The impact of osteoporosis in men treated for prostate cancer. Urol Clin North Am 2004; 31: 313–319.

    Article  Google Scholar 

  7. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ . Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999; 20: 345–357.

    Article  CAS  Google Scholar 

  8. Zaidi M . Skeletal remodeling in health and disease. Nat Med 2007; 13: 791–801.

    Article  CAS  Google Scholar 

  9. Hofbauer LC, Schoppet M . Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490–495.

    Article  CAS  Google Scholar 

  10. Clines GA, Guise TA . Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 2008; 10: e7.

    Article  Google Scholar 

  11. Saylor PJ, Smith MR . Bone health and prostate cancer. Prostate Cancer Prostatic Dis 2010; 13: 20–27.

    Article  CAS  Google Scholar 

  12. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N . Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169: 2008–2012.

    Article  CAS  Google Scholar 

  13. Ryan CW, Huo D, Bylow K, Demers LM, Stadler WM, Henderson TO et al. Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid. BJU Int 2007; 100: 70–75.

    Article  CAS  Google Scholar 

  14. Michaelson MD, Kaufman DS, Lee H, McGovern FJ, Kantoff PW, Fallon MA et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 2007; 25: 1038–1042.

    Article  CAS  Google Scholar 

  15. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–1468.

    Article  CAS  Google Scholar 

  16. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879–882.

    Article  CAS  Google Scholar 

  17. Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361: 745–755.

    Article  CAS  Google Scholar 

  18. Smith MR, Saad F, Egerdie B, Szwedowski M, Tammela TL, Ke C et al. Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 2009; 182: 2670–2675.

    Article  CAS  Google Scholar 

  19. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813–822.

    Article  CAS  Google Scholar 

  20. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2011; 379: 39–46.

    Article  Google Scholar 

  21. Carducci MA, Jimeno A . Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res 2006; 12 (20 Pt 2): 6296s–6300s.

    Article  CAS  Google Scholar 

  22. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS . Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006; 106: 581–588.

    Article  CAS  Google Scholar 

  23. Galsky MD, Vogelzang NJ . Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol 2010; 21: 2135–2144.

    Article  CAS  Google Scholar 

  24. Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD et al. 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 2003; 21: 679–689.

    Article  CAS  Google Scholar 

  25. Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; 110: 1959–1966.

    Article  CAS  Google Scholar 

  26. Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 2008; 113: 2478–2487.

    Article  CAS  Google Scholar 

  27. Quinn David I, Tangen Catherine M, Hussain Maha, Lara Primo N, Goldkorn Amir, Garzotto Mark et al. SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC). J Clin Oncol 2012; (suppl; abstr 4511).

  28. James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol 2009; 55: 1112–1123.

    Article  CAS  Google Scholar 

  29. Fizazi KS, Higano CS, Nelson JB, Gleave M, Miller K, Morris T et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2013; 31: 1740–1747.

    Article  CAS  Google Scholar 

  30. Miller K, Moul JW, Gleave M, Fizazi K, Nelson JB, Morris T et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 2013; 16: 187–192.

    Article  CAS  Google Scholar 

  31. Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS . Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Res 2002; 62: 1370–1376.

    CAS  PubMed  Google Scholar 

  32. Smith MR, Morton RA, Barnette KG, Sieber PR, Malkowicz SB, Rodriguez D et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 2013; 189 (1 Suppl): S45–S50.

    CAS  PubMed  Google Scholar 

  33. Finlay IG, Mason MD, Shelley M . Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol 2005; 6: 392–400.

    Article  CAS  Google Scholar 

  34. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007; 8: 587–594.

    Article  CAS  Google Scholar 

  35. Tomblyn M . The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases. Cancer Control 2012; 19: 137–144.

    Article  CAS  Google Scholar 

  36. Cheetham PJ, Petrylak DP . Alpha particles as radiopharmaceuticals in the treatment of bone metastases: mechanism of action of radium-223 chloride (Alpharadin) and radiation protection. Oncology (Williston Park) 2012; 26: 330–337 341.

    Google Scholar 

  37. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007; 8: 587–594.

    Article  CAS  Google Scholar 

  38. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–223.

    Article  CAS  Google Scholar 

  39. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM . Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 2009; 15: 2207–2214.

    Article  CAS  Google Scholar 

  40. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM . Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003; 3: 347–361.

    Article  Google Scholar 

  41. Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology 2002; 60: 1113–1117.

    Article  Google Scholar 

  42. Tu WH, Zhu C, Clark C, Christensen JG, Sun Z . Efficacy of c-Met inhibitor for advanced prostate cancer. BMC Cancer 2010; 10: 556.

    Article  Google Scholar 

  43. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10: 2298–2308.

    Article  CAS  Google Scholar 

  44. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31: 412–419.

    Article  CAS  Google Scholar 

  45. Fizazi K . The role of Src in prostate cancer. Ann Oncol 2007; 18: 1765–1773.

    Article  CAS  Google Scholar 

  46. Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 2005; 65: 9185–9189.

    Article  CAS  Google Scholar 

  47. Yu EY, Wilding G, Posadas E, Gross M, Culine S, Massard C et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 2009; 15: 7421–7428.

    Article  CAS  Google Scholar 

  48. Araujo John C, Trudel Geralyn C, Saad Fred, Armstrong Andrew J, Yu Evan Y, Bellmunt Joaquim et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. J Clin Oncol 2013; 31, (suppl 6; abstr LBA8).

  49. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

    Article  CAS  Google Scholar 

  50. Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN 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 2012; 13: 1210–1217.

    Article  CAS  Google Scholar 

  51. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    Article  CAS  Google Scholar 

  52. Fizazi K, HI Scher, Saad F et al. Impact of Enzalutamide, an androgen receptor signaling inhibitor, on time to first skeletal related event (SRE) and pain in the phase 3 AFFIRM study. Ann Oncol 2012; 23, (suppl 9; abstract 8960).

  53. Boyle WJ, Simonet WS, Lacey DL . Osteoclast differentiation and activation. Nature 2003; 423: 337–342.

    Article  CAS  Google Scholar 

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Albany, C., Hahn, N. Novel bone-targeting agents in prostate cancer. Prostate Cancer Prostatic Dis 17, 112–118 (2014). https://doi.org/10.1038/pcan.2014.12

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