Upcoming Challenges

Our knowledge of the mechanisms driving the progression of prostate cancer is growing. Although several new therapies that target both the cancer cells and the supporting microenvironment and are likely to increase overall survival rates for men with mCRPC, new challenges are also emerging, particularly within the context of tumor heterogeneity.

Heterogeneity is a key aspect of cancer evolution and is a clinical reality in many cancers, including prostate cancer.124-126 Greater heterogeneity facilitates the evolution of the treatment resistance of cancer but also gives the cancer a number of phenotypic strategies that allow for growth in select microenvironments (eg, bone).


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Emerging studies suggest that most patients would be best served by therapies tailored toward cancer cells harboring common aberrations as well as by therapies geared toward smaller subpopulations who could potentially become the dominant-resistant population.127

The therapies described herein constitute new ways in which to expand the number of potential options for the treatment of heterogeneous bone metastatic CRPCs. However, a challenge emerging with the advent of these therapies is how to rationally design a treatment strategy for individual patients. Current guidelines from the National Comprehensive Cancer Network provide recommendations for applying the sequence of existing therapies to patients with mCRPC based on individual patient parameters.

However, some studies suggest that altering the sequence or the combination of existing therapies can have a profound impact on overall survival rates.128

To circumvent costly and time-consuming clinical trials assessing the combination and sequence alterations of a new line of targeted therapies currently in clinical trials, alternative approaches are required. In this regard, integrating computational models and genetic algorithms with individual patient-derived biological data might lead to the rapid optimization of therapy choice and sequence. In the preclinical setting, the power of this integrated approach has been demonstrated.

Recent studies have discovered how appropriate drug combinations guided by com­ putational models could minimize prostate cancer progression in vivo.129 Therefore, the refinement and validation of these approaches may assist in overcom­ing the challenges posed by cancer heterogeneity.

Conclusions

Metastatic castration-resistant prostate cancer is an incurable disease, but the advent of new therapies, combined with an enhanced understanding of the underlying biology, suggests that significant improvement in overall survival is within reach.

An increase in the number of available treatment options will be challenging from a clinical perspective with regard to patient stratification and in selecting the optimal therapy sequence, combination, or both.

However, integrating computational models and genetic algorithms based on individual patient data may help overcome this challenge and allow for the delivery of individualized treatment for patients with this disease.


Jeremy S. Frieling, David Basanta, PhD, and Conor C. Lynch, PhD 

From the Departments of Tumor Biology (JSF, CCL) and Integrated Mathematical Oncology (DB), H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 

Submitted August 6, 2014; accepted September 11, 2014. 

Address correspondence to Conor C. Lynch, PhD, Department of Tumor Biology, Moffitt Cancer Center, 12902 Magnolia Drive, SRB-3, Tampa, FL 33612. E-mail: [email protected] 

No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 

This work was supported in part by funding support that Dr Lynch received from the National Cancer Institute (RO1CA143094). 


References

  1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014.
  2. American Cancer Society. Survival rates for prostate cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-surviv­al-rates. Accessed October 15, 2014.
  3. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297.
  4. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castra­tion-resistant prostate cancer. Nat Rev Clin Oncol. 2011;8(1):12-23.
  5. Cookson MS, Roth BJ, Dahm P, et al; American Urological Association (AUA). Castration-Resistant Prostate Cancer. Linthicum, MD: AUA; 2014. https://www.auanet.org/common/pdf/education/clinical-guidance/Castra­tion-Resistant-Prostate-Cancer.pdf. Accessed October 15, 2014.
  6. Huang X, Chau CH, Figg WD. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures. J Hematol Oncol. 2012;5:35.
  7. American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/cancer/prostatecancer/detailedguide/pros­tate-cancer-key-statistics. Accessed October 15, 2014.
  8. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004;91(4):718-729.
  9. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583.
  10. Crawford ED, Petrylak D. Castration-resistant prostate cancer: descrip­tive yet pejorative? J Clin Oncol. 2010;28(23):e408.
  11. Benjamin R. Neurologic complications of prostate cancer. Am Fam Physician. 2002;65(9):1834-1840.
  12. American Cancer Society. Preventing and treating prostate cancer spread to bone. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-treating-pain. Accessed October 15, 2014.
  13. Tomblyn M. The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases. Cancer Control. 2012;19(2):137-144.
  14. Iagaru A, Young P, Mittra E, et al. Pilot prospective evaluation of 99mTc- MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clin Nucl Med. 2013;38(7):e290-296.
  15. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estra­mustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520.
  16. Agarwal N, Di Lorenzo G, Sonpavde G, et al. New agents for prostate cancer. Ann Oncol. 2014;25(9):1700-1709.
  17. American Cancer Society. Prednisone. http://www.cancer.org/treatment/ treatmentsandsideeffects/guidetocancerdrugs/prednisone. Accessed October 15, 2014.
  18. National Comprehensive Cancer Network. NCCN clinical practice guidelines in prostate cancer. Version 2.2014. http://www.nccn.org. Accessed October 15, 2014.
  19. Egan A, Dong Y, Zhang H, et al. Castration-resistant prostate cancer: adaptive responses in the androgen axis. Cancer Treat Rev. 2014;40(3):426-433.
  20. Chang KH, Li R, Papari-Zareei M, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2011;108(33):13728-13733.
  21. Ishizaki F, Nishiyama T, Kawasaki T, et al. Androgen deprivation pro­motes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer. Sci Rep. 2013;3:1528.
  22. Chang KH, Li R, Kuri B, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013;154(5):1074-1084.
  23. de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-302 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
  24. Ryan CJ, Smith MR, de Bono JS, et al; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
  25. Pinto Á. Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer. Cancer Biol Ther. 2014;15(2):149-155.
  26. US Food and Drug Administration. Enzalutamide (XTANDI capsules). http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm317997.htm. Accessed October 15, 2014.
  27. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.
  28. Fizazi K, Albiges L, Massard C, et al. Novel and bone-targeted agents for CRPC. Ann Oncol. 2012;23(suppl 10):x264-x267.
  29. Tran C, Ouk S, Clegg NJ, et al. Development of a second-genera­tion antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790.
  30. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate vancer before chemotherapy. N Engl J Med. 2014371(5):424-433.
  31. de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-la­bel trial. Lancet. 2010;376(9747):1147-1154.
  32. Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
  33. Saad F, Gleason DM, Murray R, et al; Zoledronic Acid Prostate Cancer Study Group. 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(11):879-882.
  34. Fizazi K, Carducci M, Smith M, 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(9768):813-822.
  35. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
  36. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  37. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15(2):723-730.
  38. National Cancer Institute. FDA approval for cabazitaxel. National Cancer Institute. 2013. http://www.cancer.gov/cancertopics/druginfo/fda-cabazitaxel. Accessed October 15, 2014.
  39. National Cancer Institute. FDA approval for sipuleucel-T. http://www.cancer.gov/cancertopics/druginfo/fda-sipuleucel-T. Accessed October 15, 2014.
  40. Schweizer MT, Drake CG. Immunotherapy for prostate cancer: recent developments and future challenges. Cancer Metastasis Rev. 2014;33(2- 3):641-655.
  41. Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer. 1997;80(8 suppl):1652-1660.
  42. National Cancer Institute. FDA approval for denosumab. http://www.cancer.gov/cancertopics/druginfo/fda-denosumab. Accessed October 15, 2014.
  43. Helo S, Manger JP, Krupski TL. Role of denosumab in prostate cancer. Prostate Cancer Prostatic Dis. 2012;15(3):231-236.
  44. Armstrong AP, Miller RE, Jones JC, et al. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008;68(1):92-104.
  45. Miller RE, Roudier M, Jones J, et al. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther. 2008;7(7):2160-2169.
  46. National Cancer Institute. FDA approval for radium 223 dichloride. http:// www.cancer.gov/cancertopics/druginfo/fda-radium-223-dichloride. Accessed October 15, 2014.
  47. 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(4):330-337, 341.
  48. De Wit R FK, Jinga V, Efstathiou E, et al. Phase 3, randomized, pla­cebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC4 trial). J Clin Oncol. 2014;32(suppl 5):5008.
  49. Dreicer R JR, Oudard S, Efstathiou E, 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-PC5 trial). J Clin Oncol. 2014;32(suppl 4):7.
  50. Osanto S, van Poppel H, Burggraaf J. Tasquinimod: a novel drug in advanced prostate cancer. Future Oncol. 2013;9(9):1271-1281.
  51. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412-419.
  52. Saad F, Hotte S, North S, et al; Canadian Uro-Oncology Group. Ran­domized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-re­sistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin Cancer Res. 2011;17(17):5765-5773.
  53. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
  54. Slovin SF, Higano CS, Hamid O, 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. 2013;24(7):1813-1821.
  55. Gerritsen WR, Sharma P. Current and emerging treatment options for castration-resistant prostate cancer: a focus on immunotherapy. J Clin Immunol. 2012;32(1):25-35.
  56. Gulley JL, Arlen PM, Madan RA, et al. Immunologic and prognostic fac­tors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010;59(5):663-674.
  57. Pili R, Häggman M, Stadler WM, 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. 2011;29(30):4022-4028.
  58. Yamaoka M, Hara T, Hitaka T, et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012;129(3-5):115-128.
  59. Agus DB SW, Shevrin DH, Hart L, et al. Safety, efficacy, and pharma­codynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): updated data from a phase I/ II study. J Clin Oncol. 2012;30(suppl 5):98.
  60. Jennbacken K, Welén K, Olsson A, et al. Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050). Prostate. 2012;72(8):913-924.
  61. Hiratsuka S, Watanabe A, Aburatani H, et al. Tumour-mediated upreg­ulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol. 2006;8(12):1369-1375.
  62. Hiratsuka S, Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol. 2008;10(11):1349-1355.
  63. Olsson A, Björk A, Vallon-Christersson J, et al. Tasquinimod (ABR- 215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors. Mol Cancer. 2010;9:107.
  64. Scher HI, Smith MR, Sweeney C, et al. An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): updated results of a phase II non­randomized expansion (NRE) cohort. J Clin Oncol. 2013;31(suppl):5026.
  65. Cochrane DR, Wang Z, Muramaki M, et al. Differential regulation of clusterin and its isoforms by androgens in prostate cells. J Biol Chem. 2007;282(4):2278-2287.
  66. Zellweger T, Chi K, Miyake H, et al. Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin Cancer Res. 2002;8(10):3276-3284.
  67. Chi KN, Bjartell A, Dearnaley D, et al. Castration-resistant pros­tate cancer: from new pathophysiology to new treatment targets. Eur Urol. 2009;56(4):594-605.
  68. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castra­tion-resistant prostate cancer. J Clin Oncol. 2010;28(27):4247-4254.
  69. Higano CS. Potential use of custirsen to treat prostate cancer. Onco Targets Ther. 2013;6:785-797.
  70. Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs. 2009;18(7):1001-1011.
  71. DiPaola RS, Plante M, Kaufman H, et al. A phase I trial of pox PSA vaccines (PROSTVAC-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory mol­ecules (TRICOM) in patients with prostate cancer. J Transl Med. 2006;4:1.
  72. Kantoff PW, Schuetz TJ, Blumenstein BA, 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. 2010;28(7):1099-1105.
  73. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 li­gands, and other features of the tumor immune microenvironment with re­sponse to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-5074.
  74. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.
  75. Peinado H, Alečković M, Lavotshkin S, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883-891.
  76. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haema­topoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820-827.
  77. Webber J, Steadman R, Mason MD, et al. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70(23):9621-9630.
  78. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569-579.
  79. Di Vizio D, Kim J, Hager MH, et al. Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in meta­static disease. Cancer Res. 2009;69(13):5601-5609.
  80. Di Vizio D, Morello M, Dudley AC, et al. Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol. 2012;181(5):1573-1584.
  81. Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005;105(7):2631-2639.
  82. Paget G. Remarks on a case of alternate partial anaesthesia. Br Med J. 1889;1(1462):1-3.
  83. Ewing J. Neoplastic Diseases. 6th ed. Philadelphia: W.B. Saunders; 1928.
  84. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453-458.
  85. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980;283(5743):139-146.
  86. Roudier MP, Vesselle H, True LD, et al. Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results. Clin Exp Metastasis. 2003;20(2):171-180.
  87. Lapidot T, Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplant­ed immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia. 2002;16(10):1992-2003.
  88. Wang J, Loberg R, Taichman RS. The pivotal role of CXCL12 (SDF-1)/ CXCR4 axis in bone metastasis. Cancer Metastasis Rev. 2006;25(4):573-587.
  89. Singh RK, Lokeshwar BL. The IL-8-regulated chemokine recep­tor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res. 2011;71(9):3268-3277.
  90. Akashi T, Koizumi K, Tsuneyama K, et al. Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci. 2008;99(3):539-542.
  91. Lu Y, Cai Z, Galson DL, et al. Monocyte chemotactic protein-1 (MCP- 1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate. 2006;66(12):1311-1318.
  92. Lu Y, Wang J, Xu Y, et al. CXCL16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol Cancer Res. 2008;6(4):546-554.
  93. Shiozawa Y, Havens AM, Pienta KJ, et al. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia. 2008;22(5):941-950.
  94. Vessella RL, Pantel K, Mohla S. Tumor cell dormancy: an NCI workshop report. Cancer Bio Ther. 2007;6(9):1496-1504.
  95. Lam HM, Vessella RL, Morrissey C. The role of the microenviron­ment-dormant prostate disseminated tumor cells in the bone marrow. Drug Discov Today Technol. 2014;11:41-47.
  96. Shiozawa Y, Havens AM, Jung Y, et al. Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem. 2008;105(2):370-380.
  97. Shiozawa Y, Pedersen EA, Patel LR, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia. 2010;12(2):116-127.
  98. Taichman RS, Patel LR, Bedenis R, et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS One. 2013;8(4):e61873.
  99. Dormady SP, Zhang XM, Basch RS. Hematopoietic progenitor cells grow on 3T3 fibroblast monolayers that overexpress growth arrest-specific gene-6 (GAS6). Proc Natl Acad Sci U S A. 2000;97(22):12260-12265.
  100. Kim JK, Jung Y, Wang J, et al. TBK1 regulates prostate cancer dor­mancy through mTOR inhibition. Neoplasia. 2013;15(9):1064-1074.
  101. Bragado P, Sosa MS, Keely P, et al. Microenvironments dictating tumor cell dormancy. Recent Results Cancer Res. 2012;195:25-39.
  102. Bragado P, Estrada Y, Parikh F, et al. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38β/β signalling. Nat Cell Biol. 2013;15(11):1351-1361.
  103. Kobayashi A, Okuda H, Xing F, et al. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011;208(13):2641-2655.
  104. Ghajar CM, Peinado H, Mori H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013;15(7):807-817.
  105. Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298-1312.
  106. Pedersen EA, Shiozawa Y, Pienta KJ, et al. The prostate cancer bone marrow niche: more than just ‘fertile soil’. Asian J Androl. 2012;14(3):423-427.
  107. Hershberger PM, Peddibhotla S, Sugarman E, et al. Probing the CXCR6/CXCL16 Axis: targeting prevention of prostate cancer metastasis. Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information; 2012.
  108. Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of pros­tate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39(4):246-261.
  109. Thomas R, True LD, Bassuk JA, et al. Differential expression of osteo­nectin/SPARC during human prostate cancer progression. Clin Cancer Res. 2000;6(3):1140-1149.
  110. Lin DL, Tarnowski CP, Zhang J, et al. Bone metastatic LNCaP-derivative C4-2B prostate cancer cell line mineralizes in vitro. Prostate. 2001;47(3):212-221.
  111. Chu GC, Chung LW. RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev. 2014;33(2-3):497-509.
  112. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80(8 sup­pl):1546-1556.
  113. Roudier MP, Morrissey C, True LD, et al. Histopathological assessment of prostate cancer bone osteoblastic metastases. J Urol. 2008;180(3):1154-1160.
  114. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584-593.
  115. Lynch CC. Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Bone. 2011;48(1):44-53.
  116. Faccio R. Immune regulation of the tumor/bone vicious cycle. Ann N Y Acad Sci. 2011;1237:71-78.
  117. Casimiro S, Guise TA, Chirgwin J. The critical role of the bone micro­environment in cancer metastases. Mol Cell Endocrinol. 2009;310(1-2):71-81.
  118. Cook LM, Shay G, Aruajo A, et al. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33(2-3):511-525.
  119. Lynch CC, Vargo-Gogola T, Martin MD, et al. Matrix metalloproteinase 7 mediates mammary epithelial cell tumorigenesis through the ErbB4 receptor. Cancer Res. 2007;67(14):6760-6767.
  120. Thiolloy S, Edwards JR, Fingleton B, et al. An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment. PLoS One. 2012;7(1):e29862.
  121. Bruni-Cardoso A, Johnson LC, Vessella RL, et al. Osteoclast-derived matrix metalloproteinase-9 directly affects angiogenesis in the prostate tu­mor-bone microenvironment. Mol Cancer Res. 2010;8(4):459-470.
  122. Tauro M, McGuire J, Lynch CC. New approaches to selectively target cancer associated matrix metalloproteinase activity. Cancer Metastasis Rev. 2014. [In press].
  123. Esposito M, Kang Y. Targeting tumor-stromal interactions in bone me­tastasis. Pharmacol Ther. 2014;141(2):222-233.
  124. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing [Erratum appears in N Engl J Med. 2012;367(10):976]. N Engl J Med. 2012;366(10):883-892.
  125. Gerlinger M, Catto JW, Orntoft TF, et al. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. Eur Urol. 2014. [Epub ahead of print].
  126. Drake JM, Graham NA, Lee JK, et al. Metastatic castration-re­sistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. Proc Natl Acad Sci U S A. 2013;110(49):E4762-E4769.
  127. Gallaher J, Cook LM, Gupta S, et al. Improving treatment strategies for patients with metastatic castrate resistant prostate cancer through personalized computational modeling. Clin Exp Metastasis. 2014. [Epub ahead of print].
  128. Sweeney C, Chen YH, Carduccie MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sen­sitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase 3 ran­domized trial. J Clin Oncol. 2014;32(5 suppl):LBA2.
  129. Zhao B, Pritchard JR, Lauffenburger DA, et al. Addressing genetic tumor heterogeneity through computationally predictive combination therapy. Cancer Discov. 2014;4(2):166-174.

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