Skip to main content

Advertisement

Log in

Emerging targeted therapies for bladder cancer: a disease waiting for a drug

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Urothelial cell carcinoma is the fifth most common cancer and the costliest to treat. This is largely because of all new cases, about 70% present as superficial disease and this while rarely fatal, tends to recur, requiring long-term follow-up and repeat interventions. The standard of care, intravesical chemo- and immunotherapy, while effective, is associated with a considerable side-effect profile and approximately 30% of patients either fail to respond to treatment or suffer recurrent disease within 5 years. Muscle-invasive bladder cancer is life threatening, showing modest chemosensitivity, and usually requires radical cystectomy. Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors such as lung, breast and prostate, been few in number and largely unsuccessful, with no new agents being registered in the last 20 years. Hence, bladder cancer represents a considerable opportunity and challenge for molecularly targeted therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., & Thun, M. J. (2009). Cancer statistics, 2009. CA: A Cancer Journal for Clinicians, 59, 225–249.

    Google Scholar 

  2. Wu, X. R. (2005). Urothelial tumorigenesis: a tale of divergent pathways. Nature Reviews Cancer, 5, 713–725.

    CAS  PubMed  Google Scholar 

  3. Zhang, Z. T., Pak, J., Huang, H. Y., Shapiro, E., Sun, T. T., Pellicer, A., et al. (2001). Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene, 20, 1973–1980.

    CAS  PubMed  Google Scholar 

  4. Zhang, Z. T., Pak, J., Shapiro, E., Sun, T. T., & Wu, X. R. (1999). Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Research, 59, 3512–3517.

    CAS  PubMed  Google Scholar 

  5. Sievert, K. D., Amend, B., Nagele, U., et al. (2009). Economic aspects of bladder cancer: what are the benefits and costs? World Journal of Urology, 27, 295–300.

    CAS  PubMed  Google Scholar 

  6. Botteman, M. F., Pashos, C. L., Redaelli, A., Laskin, B., & Hauser, R. (2003). The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics, 21, 1315–1330.

    PubMed  Google Scholar 

  7. Zou, W. (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews Cancer, 5, 263–274.

    CAS  PubMed  Google Scholar 

  8. Malmström, P., Sylvester, R. J., Crawford, D. E., et al. (2009). An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus Bacillus Calmette–Guérin for non-muscle-invasive bladder cancer. European Urology, 56, 247–256.

    PubMed  Google Scholar 

  9. Ponticiello, A., Perna, F., Maione, S., et al. (2004). Analysis of local T lymphocyte subsets upon stimulation with intravesical BCG: a model to study tuberculosis immunity. Respiratory Medicine, 98, 509–514.

    PubMed  Google Scholar 

  10. Naoe, M., Ogawa, Y., Takeshita, K., Morita, J., Iwamoto, S., Miyazaki, A., et al. (2007). Bacillus Calmette–Guerin-pulsed dendritic cells stimulate natural killer T cells and gammadeltaT cells. International Journal of Urology, 14, 532. 8; discussion 538.

    CAS  PubMed  Google Scholar 

  11. van der Meijden, A. P. M., Sylvester, R. J., Oosterlinck, W., Hoeltl, W., & Bono, A. V. (2003). Maintenance Bacillus Calmette–Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. European Urology, 44, 429–434.

    PubMed  Google Scholar 

  12. Saint, F., Patard, J. J., Maille, P., et al. (2001). T Helper 1/2 lymphocyte urinary cytokine profiles in responding and non-responding patients after 1 and 2 courses of Bacillus Calmette–Guerin for superficial bladder cancer. Journal of Urology, 166, 2142–2147.

    CAS  PubMed  Google Scholar 

  13. Nadler, R., Luo, Y., Zhao, W., et al. (2003). Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis Bacillus Calmette–Guerin (BCG) mediated antitumour activity. Clinical and Experimental Immunology, 131, 206–216.

    CAS  PubMed  Google Scholar 

  14. Saint, F., Patard, J. J., Maille, P., et al. (2002). Prognostic value of a T helper 1 urinary cytokine response after intravesical Bacillus Calmette–Guerin treatment for superficial bladder cancer. Journal of Urology, 167, 364–367.

    PubMed  Google Scholar 

  15. Luo, Y., Chen, X., Downs, T. M., DeWolf, W. C., & O'Donnell, M. A. (1999). IFN-{alpha} 2B enhances Th1 cytokine responses in bladder cancer patients receiving mycobacterium bovis Bacillus Calmette–Guerin immunotherapy. Journal of Immunology, 162, 2399–2405.

    CAS  Google Scholar 

  16. Papageorgiou, A., Lashinger, L., Millikan, R., Grossman, H. B., Benedict, W., Dinney, C. P., et al. (2004). Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells. Cancer Research, 64, 8973–8979.

    CAS  PubMed  Google Scholar 

  17. Papageorgiou, A., Kamat, A., Benedict, W. F., Dinney, C., & McConkey, D. J. (2006). Combination therapy with IFN-alpha plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells. Molecular Cancer Therapeutics, 5, 3032–3041.

    CAS  PubMed  Google Scholar 

  18. Gallagher, B. L., Joudi, F. N., Maymí, J. L., & O’Donnell, M. A. (2008). Impact of previous Bacille Calmette–Guérin failure pattern on subsequent response to Bacille Calmette–Guérin plus interferon intravesical therapy. Urology, 71, 297–301.

    PubMed  Google Scholar 

  19. Nepple, K. G., Aubert, H. A., Braasch, M. R., & O'Donnell, M. A. (2009). Combination of BCG and interferon intravesical immunotherapy: an update. World Journal of Urology, 27, 343–346.

    CAS  PubMed  Google Scholar 

  20. Mohammed, S. I., Knapp, D. W., Bostwick, D. G., et al. (1999). Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of the urinary bladder. Cancer Research, 59, 5647–5650.

    CAS  PubMed  Google Scholar 

  21. Wheeler, M. A., Hausladen, D. A., Yoon, J. H., & Weiss, R. M. (2002). Prostaglandin E2 production and cyclooxygenase-2 induction in human urinary tract infections and bladder cancer. Journal of Urology, 168, 1568–1573.

    CAS  PubMed  Google Scholar 

  22. Kim, S Il, Kwon, S. M., Kim, Y. S., & Hong, S. J. (2002). Association of cyclooxygenase-2 expression with prognosis of stage T1 grade 3 bladder cancer. Urology, 60, 816–821.

    PubMed  Google Scholar 

  23. Krysan, K., Reckamp, K. L., Dalwadi, H., Sharma, S., Rozengurt, E., Dohadwala, M., et al. (2005). Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Research, 65, 6275–6281.

    CAS  PubMed  Google Scholar 

  24. Wang, D., Buchanan, F. G., Wang, H., Dey, S. K., & DuBois, R. N. (2005). Prostaglandin E2 enhances intestinal adenoma growth via activation of the Ras-mitogen-activated protein kinase cascade. Cancer Research, 65, 1822–1829.

    CAS  PubMed  Google Scholar 

  25. Pai, R., Soreghan, B., Szabo, I. L., Pavelka, M., Baatar, D., & Tarnawski, A. S. (2002). Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Medicine, 8, 289–293.

    CAS  PubMed  Google Scholar 

  26. Herfs, M., Herman, L., Hubert, P., et al. (2009). High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells. Cancer Immunology, Immunotherapy, 58, 603–614.

    CAS  PubMed  Google Scholar 

  27. Sharma, S., Yang, S., Zhu, L., et al. (2005). Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer. Cancer Research, 65, 5211–5220.

    CAS  PubMed  Google Scholar 

  28. Harizi, H., Juzan, M., Pitard, V., Moreau, J. F., & Gualde, N. (2002). Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. Journal of Immunology, 168, 2255–2263.

    CAS  Google Scholar 

  29. Dovedi, S. J., Kirby, J. A., Atkins, H., Davies, B. R., & Kelly, J. D. (2005). Cyclooxygenase-2 inhibition: a potential mechanism for increasing the efficacy of Bacillus Calmette–Guerin immunotherapy for bladder cancer. Journal of Urology, 174, 332. 7; discussion 337.

    CAS  PubMed  Google Scholar 

  30. Dovedi, S. J., Kirby, J. A., Davies, B. R., Leung, H., & Kelly, J. D. (2008). Celecoxib has potent antitumour effects as a single agent and in combination with BCG immunotherapy in a model of urothelial cell carcinoma. European Urology, 54, 621–630.

    CAS  PubMed  Google Scholar 

  31. Chambers, M., Marshall, B., Wangoo, A., Bune, A., Cook, H., Shaw, R., et al. (1997). Differential responses to challenge with live and dead Mycobacterium bovis Bacillus Calmette–Guerin. Journal of Immunology, 158, 1742–1748.

    CAS  Google Scholar 

  32. Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388, 394–397.

    CAS  PubMed  Google Scholar 

  33. Atkins, H., Davies, B. R., Kirby, J. A., & Kelly, J. D. (2003). Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy. British Journal of Cancer, 89, 2312–2319.

    CAS  PubMed  Google Scholar 

  34. Olbert, P. J., Schrader, A. J., Simon, C., Dalpke, A., Barth, P., Hofmann, R., et al. (2009). In vitro and in vivo effects of CpG-Oligodeoxynucleotides (CpG-ODN) on murine transitional cell carcinoma and on the native murine urinary bladder wall. Anticancer Research, 29, 2067–2076.

    CAS  PubMed  Google Scholar 

  35. Mangsbo, S. M., Ninalga, C., Essand, M., Loskog, A., & Totterman, T. H. (2008). CpG therapy is superior to BCG in an orthotopic bladder cancer model and generates CD4+ T-cell immunity. Journal of Immunotherapy, 31, 34–42.

    PubMed  Google Scholar 

  36. Filion, M. C., Lepicier, P., Morales, A., & Phillips, N. C. (1999). Mycobacterium phlei cell wall complex directly induces apoptosis in human bladder cancer cells. British Journal of Cancer, 79, 229–235.

    CAS  PubMed  Google Scholar 

  37. Kanehira, M., Harada, Y., Takata, R., et al. (2007). Involvement of upregulation of DEPDC1 (DEP domain containing 1) in bladder carcinogenesis. Oncogene, 26, 6448–6455.

    CAS  PubMed  Google Scholar 

  38. Kanehira, M., Katagiri, T., Shimo, A., et al. (2007). Oncogenic role of MPHOSPH1, a cancer-testis antigen specific to human bladder cancer. Cancer Research, 67, 3276–3285.

    CAS  PubMed  Google Scholar 

  39. Bergeron, A., Picard, V., LaRue, H., Harel, F., Hovington, H., Lacombe, L., et al. (2009). High frequency of MAGE-A4 and MAGE-A9 expression in high-risk bladder cancer. International Journal of Cancer, 125, 1365–1371.

    CAS  Google Scholar 

  40. Sharma, P., Bajorin, D. F., Jungbluth, A. A., Herr, H., Old, L. J., & Gnjatic, S. (2008). Immune responses detected in urothelial carcinoma patients after vaccination with NY-ESO-1 protein plus BCG and GM-CSF. Journal of Immunotherapy, 31, 849–857.

    CAS  PubMed  Google Scholar 

  41. Cappellen, D., De Oliveira, C., Ricol, D., et al. (1999). Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genetics, 23, 18–20.

    CAS  PubMed  Google Scholar 

  42. Billerey, C., Chopin, D., Aubriot-Lorton, M. H., et al. (2001). Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. American Journal of Pathology, 158, 1955–1959.

    CAS  PubMed  Google Scholar 

  43. van Rhijn, B. W., Lurkin, I., Radvanyi, F., Kirkels, W. J., van der Kwast, T. H., & Zwarthoff, E. C. (2001). The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Research, 61, 1265–1268.

    PubMed  Google Scholar 

  44. Tomlinson, D. C., Baldo, O., Harnden, P., & Knowles, M. A. (2007). FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. Journal of Pathology, 213, 91–98.

    CAS  PubMed  Google Scholar 

  45. Bernard-Pierrot, I., Brams, A., Dunois-Larde, C., et al. (2006). Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis, 27, 740–747.

    CAS  PubMed  Google Scholar 

  46. Tomlinson, D. C., Hurst, C. D., & Knowles, M. A. (2007). Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene, 26, 5889–5899.

    CAS  PubMed  Google Scholar 

  47. Chaffer, C. L., Brennan, J. P., Slavin, J. L., Blick, T., Thompson, E. W., & Williams, E. D. (2006). Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Research, 66, 11271–11278.

    CAS  PubMed  Google Scholar 

  48. Diez de Medina SG, Chopin, D., El Marjou, A., et al. (1997). Decreased expression of keratinocyte growth factor receptor in a subset of human transitional cell bladder carcinomas. Oncogene, 14, 323–330.

    CAS  PubMed  Google Scholar 

  49. Tomlinson, D. C., Lamont, F. R., Shnyder, S. D., & Knowles, M. A. (2009). Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer. Cancer Research, 69, 4613–4620.

    CAS  PubMed  Google Scholar 

  50. Qing, J., Du, X., Chen, Y., et al. (2009). Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. Journal of Clinical Investigation, 119, 1216–1229.

    CAS  PubMed  Google Scholar 

  51. Jebar, A. H., Hurst, C. D., Tomlinson, D. C., Johnston, C., Taylor, C. F., & Knowles, M. A. (2005). FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene, 24, 5218–5225.

    CAS  PubMed  Google Scholar 

  52. Platt, F. M., Hurst, C. D., Taylor, C. F., Gregory, W. M., Harnden, P., & Knowles, M. A. (2009). Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clinical Cancer Research, 15, 6008–6017.

    CAS  PubMed  Google Scholar 

  53. Winquist, E., Moore, M. J., Chi, K. N., et al. (2005). A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer. Urol Oncol, 23, 143–149.

    CAS  PubMed  Google Scholar 

  54. Rosenberg, J. E., von der Maase, H., Seigne, J. D., et al. (2005). A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma. Cancer, 103, 2035–2041.

    CAS  PubMed  Google Scholar 

  55. Brunner, T. B., Hahn, S. M., Gupta, A. K., Muschel, R. J., McKenna, W. G., & Bernhard, E. J. (2003). Farnesyltransferase inhibitors: an overview of the results of preclinical and clinical investigations. Cancer Research, 63, 5656–5668.

    CAS  PubMed  Google Scholar 

  56. Davies, B. R., Logie, A., McKay, J. S., et al. (2007). AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Molecular Cancer Therapeutics, 6, 2209–2219.

    CAS  PubMed  Google Scholar 

  57. Kassouf, W., Black, P. C., Tuziak, T., et al. (2008). Distinctive expression pattern of ErbB family receptors signifies an aggressive variant of bladder cancer. Journal of Urology, 179, 353–358.

    PubMed  Google Scholar 

  58. Philips, G. K., Halabi, S., Sanford, B. L., Bajorin, D., Small, E. J., & for the Cancer and Leukemia Group B. (2009). A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102. Annals of Oncology, 20, 1074–1079.

    CAS  PubMed  Google Scholar 

  59. Inoue, K., Slaton, J. W., Perrotte, P., et al. (2000). Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clinical Cancer Research, 6, 4874–4884.

    CAS  PubMed  Google Scholar 

  60. Perrotte, P., Matsumoto, T., Inoue, K., et al. (1999). Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clinical Cancer Research, 5, 257–265.

    CAS  PubMed  Google Scholar 

  61. Lynch, T. J., Bell, D. W., Sordella, R., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350, 2129–2139.

    CAS  PubMed  Google Scholar 

  62. Villares, G. J., Zigler, M., Blehm, K., Bogdan, C., McConkey, D., Colin, D., et al. (2007). Targeting EGFR in bladder cancer. World Journal of Urology, 25, 573–579.

    CAS  PubMed  Google Scholar 

  63. Jacobs, M. A., Wotkowicz, C., Baumgart, E. D., et al. (2007). Epidermal growth factor receptor status and the response of bladder carcinoma cells to erlotinib. Journal of Urology, 178, 1510–1514.

    CAS  PubMed  Google Scholar 

  64. Blehm, K. N., Spiess, P. E., Bondaruk, J. E., et al. (2006). Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clinical Cancer Research, 12, 4671–4677.

    CAS  PubMed  Google Scholar 

  65. Black, P. C., Brown, G. A., Inamoto, T., et al. (2008). Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clinical Cancer Research, 14, 1478–1486.

    CAS  PubMed  Google Scholar 

  66. Wulfing, C., Machiels, J. P., Richel, D. J., et al. (2009). A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer, 115, 2881–2890.

    PubMed  Google Scholar 

  67. Hussain, M. H., MacVicar, G. R., Petrylak, D. P., et al. (2007). Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. Journal of Clinical Oncology, 25, 2218–2224.

    CAS  PubMed  Google Scholar 

  68. Kim, L. C., Song, L., & Haura, E. B. (2009). Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol, 6, 587–595.

    PubMed  Google Scholar 

  69. Engelman, J. A. (2009). Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Reviews Cancer, 9, 550–562.

    CAS  PubMed  Google Scholar 

  70. Cappellen, D., Gil Diez de Medina, S., Chopin, D., Thiery, J. P., & Radvanyi, F. (1997). Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene, 14, 3059–3066.

    CAS  PubMed  Google Scholar 

  71. Cairns, P., Evron, E., Okami, K., et al. (1998). Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene, 16, 3215–3218.

    CAS  PubMed  Google Scholar 

  72. Aveyard, J. S., Skilleter, A., Habuchi, T., & Knowles, M. A. (1999). Somatic mutation of PTEN in bladder carcinoma. British Journal of Cancer, 80, 904–908.

    CAS  PubMed  Google Scholar 

  73. Wang, Z., Zhang, Z., Liu, Y., et al. (2000). Effect of retinoic acid and its complexes with transition metals on human bladder cancer cell line EJ in vitro. Urological Research, 28, 191–195.

    CAS  PubMed  Google Scholar 

  74. Tsuruta, H., Kishimoto, H., Sasaki, T., et al. (2006). Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Research, 66, 8389–8396.

    CAS  PubMed  Google Scholar 

  75. Lopez-Knowles, E., Hernandez, S., Malats, N., et al. (2006). PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Research, 66, 7401–7404.

    CAS  PubMed  Google Scholar 

  76. Knowles, M. A., Habuchi, T., Kennedy, W., & Cuthbert-Heavens, D. (2003). Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Research, 63, 7652–7656.

    CAS  PubMed  Google Scholar 

  77. Habuchi, T., Devlin, J., Elder, P. A., & Knowles, M. A. (1995). Detailed deletion mapping of chromosome 9q in bladder cancer: evidence for two tumour suppressor loci. Oncogene, 11, 1671–1674.

    CAS  PubMed  Google Scholar 

  78. Sonpavde, G., Jian, W., Liu, H., Wu, M. F., Shen, S. S., & Lerner, S. P. (2009). Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. Urol Oncol, 27, 391–399.

    CAS  PubMed  Google Scholar 

  79. Davis, D. W., Inoue, K., Dinney, C. P., Hicklin, D. J., Abbruzzese, J. L., & McConkey, D. J. (2004). Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253 J B-V bladder cancer xenografts. Cancer Research, 64, 4601–4610.

    CAS  PubMed  Google Scholar 

  80. Inoue, K., Slaton, J. W., Davis, D. W., et al. (2000). Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel. Clinical Cancer Research, 6, 2635–2643.

    CAS  PubMed  Google Scholar 

  81. Vazquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008). The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov, 7, 979–987.

    CAS  PubMed  Google Scholar 

  82. Bolderson, E., Richard, D. J., Zhou, B. B., & Khanna, K. K. (2009). Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clinical Cancer Research, 15, 6314–6320.

    CAS  PubMed  Google Scholar 

  83. Kuball, J., Wen, S. F., Leissner, J., et al. (2002). Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. Journal of Clinical Oncology, 20, 957–965.

    CAS  PubMed  Google Scholar 

  84. Hsieh, J. T., Dinney, C. P., & Chung, L. W. (2000). The potential role of gene therapy in the treatment of bladder cancer. Urologic Clinics of North America, 27, 103. 13, ix.

    CAS  PubMed  Google Scholar 

  85. Pagliaro, L. C. (2000). Gene therapy for bladder cancer. World Journal of Urology, 18, 148–151.

    CAS  PubMed  Google Scholar 

  86. Li, Y., Pong, R. C., Bergelson, J. M., et al. (1999). Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Research, 59, 325–330.

    CAS  PubMed  Google Scholar 

  87. Siemens, D. R., Crist, S., Austin, J. C., Tartaglia, J., & Ratliff, T. L. (2003). Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model. Journal of Urology, 170, 979–984.

    CAS  PubMed  Google Scholar 

  88. Fodor, I., Timiryasova, T., Denes, B., Yoshida, J., Ruckle, H., & Lilly, M. (2005). Vaccinia virus mediated p53 gene therapy for bladder cancer in an orthotopic murine model. Journal of Urology, 173, 604–609.

    CAS  PubMed  Google Scholar 

  89. Kikuchi, E., Menendez, S., Ohori, M., Cordon-Cardo, C., Kasahara, N., & Bochner, B. H. (2004). Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin. Clinical Cancer Research, 10, 1835–1842.

    CAS  PubMed  Google Scholar 

  90. Tao, Z., Connor, R. J., Ashoori, F., Dinney, C. P., Munsell, M., Philopena, J. A., et al. (2006). Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Therapy, 13, 125–130.

    CAS  PubMed  Google Scholar 

  91. Rosser, C. J., Benedict, W. F., & Dinney, C. P. (2001). Gene therapy for superficial bladder cancer. Expert Rev Anticancer Ther, 1, 531–539.

    CAS  PubMed  Google Scholar 

  92. Yamashita, M., Rosser, C. J., Zhou, J. H., et al. (2002). Syn3 provides high levels of intravesical adenoviral-mediated gene transfer for gene therapy of genetically altered urothelium and superficial bladder cancer. Cancer Gene Therapy, 9, 687–691.

    CAS  PubMed  Google Scholar 

  93. Graves, P. R., Yu, L., Schwarz, J. K., Gales, J., Sausville, E. A., O'Connor, P. M., et al. (2000). The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. Journal of Biological Chemistry, 275, 5600–5605.

    CAS  PubMed  Google Scholar 

  94. Ashwell, S., Janetka, J. W., & Zabludoff, S. (2008). Keeping checkpoint kinases in line: new selective inhibitors in clinical trials. Expert Opinion on Investigational Drugs, 17, 1331–1340.

    CAS  PubMed  Google Scholar 

  95. Zabludoff, S. D., Deng, C., Grondine, M. R., et al. (2008). AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Molecular Cancer Therapeutics, 7, 2955–2966.

    CAS  PubMed  Google Scholar 

  96. Blasina, A., Hallin, J., Chen, E., et al. (2008). Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Molecular Cancer Therapeutics, 7, 2394–2404.

    CAS  PubMed  Google Scholar 

  97. Oldenhuis, C. N., Stegehuis, J. H., Walenkamp, A. M., de Jong, S., & de Vries, E. G. (2008). Targeting TRAIL death receptors. Current Opinion in Pharmacology, 8, 433–439.

    CAS  PubMed  Google Scholar 

  98. Koschny, R., Holland, H., Sykora, J., et al. (2007). Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clinical Cancer Research, 13, 3403–3412.

    CAS  PubMed  Google Scholar 

  99. Liu, X., Yue, P., Chen, S., Hu, L., Lonial, S., Khuri, F. R., et al. (2007). The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Research, 67, 4981–4988.

    CAS  PubMed  Google Scholar 

  100. Voortman, J., Checinska, A., & Giaccone, G. (2007). The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells. Mol Cancer, 6, 73.

    PubMed  Google Scholar 

  101. Smith, M. R., Jin, F., & Joshi, I. (2007). Bortezomib sensitizes non-Hodgkin's lymphoma cells to apoptosis induced by antibodies to tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors TRAIL-R1 and TRAIL-R2. Clinical Cancer Research, 13, 5528s–5534s.

    CAS  PubMed  Google Scholar 

  102. Gomez-Abuin, G., Winquist, E., Stadler, W. M., Pond, G., Degendorfer, P., Wright, J., et al. (2007). A phase II study of PS-341 (Bortezomib) in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital and University of Chicago phase II consortia. Investigational New Drugs, 25, 181–185.

    CAS  PubMed  Google Scholar 

  103. Rosenberg, J. E., Halabi, S., Sanford, B. L., et al. (2008). Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207. Annals of Oncology, 19, 946–950.

    CAS  PubMed  Google Scholar 

  104. Kamat, A. M., Karashima, T., Davis, D. W., et al. (2004). The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo. Molecular Cancer Therapeutics, 3, 279–290.

    CAS  PubMed  Google Scholar 

  105. Nogawa, M., Yuasa, T., Kimura, S., et al. (2005). Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer. Journal of Clinical Investigation, 115, 978–985.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Barry R. Davies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dovedi, S.J., Davies, B.R. Emerging targeted therapies for bladder cancer: a disease waiting for a drug. Cancer Metastasis Rev 28, 355–367 (2009). https://doi.org/10.1007/s10555-009-9192-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-009-9192-9

Keywords

Navigation