Skip to main content

Advertisement

SpringerLink
Log in

Molecular targets and targeted therapies in bladder cancer management

  • Topic Paper
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

Bladder cancer remains a significant health problem. Currently, conventional histopathologic evaluation criteria (tumor grade and stage) are limited in their ability to accurately predict tumor behavior. A significant number of patients with muscle-invasive or extravesical disease treated by radical cystectomy alone die of metastasis. Intense research efforts are being made to better identify and categorize tumors by their molecular alterations and biological characteristics. A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma pathways that regulate the cell cycle by interacting with signal transduction pathways. Angiogenesis further contributes to the neoplastic growth by providing a constant supply of oxygen and nutrients. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor’s phenotype and subsequent clinical behavior. We provide a contemporary outline of our current understanding of the molecular and genetic events associated with tumorigenesis and progression. We emphasize the ways by which molecular biology is likely to affect the development of future therapies that will be able to target molecular alterations in individual tumors based on their respective profiles. The current status of targeted therapies for bladder cancer is also presented as well as the ongoing clinical trials.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Parkin DM (2008) The global burden of urinary bladder cancer. Scand J Urol Nephrol 42(4):12–20. doi:10.1080/03008880802285 032

    Article  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96. doi:10.3322/CA.2007.0010

    Article  PubMed  Google Scholar 

  3. Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP (2008) Superficial bladder cancer: An update on etiology, molecular development, classification, and natural history. Rev Urol 10(1):31–43

    PubMed  Google Scholar 

  4. Mitra AP, Datar RH, Cote RJ (2006) Molecular pathways in invasive bladder cancer: New insights into mechanisms, progression, and target identification. J Clin Oncol 24(35):5552–5564. doi:10.1200/JCO.2006.08.2073

    Article  PubMed  CAS  Google Scholar 

  5. Wright C, Mellon K, Johnston P, Lane DP, Harris AL, Horne CH et al (1991) Expression of mutant p53, c-erbB-2 and the epidermal growth factor receptor in transitional cell carcinoma of the human urinary bladder. Br J Cancer 63(6):967–970

    PubMed  CAS  Google Scholar 

  6. Korkolopoulou P, Christodoulou P, Kapralos P, Exarchakos M, Bisbiroula A, Hadjiyannakis M et al (1997) The role of p53, MDM2 and c-erb B-2 oncoproteins, epidermal growth factor receptor and proliferation markers in the prognosis of urinary bladder cancer. Pathol Res Pract 193(11–12):767–775

    PubMed  CAS  Google Scholar 

  7. Ravery V, Colombel M, Popov Z, Bastuji S, Patard JJ, Bellot J et al (1995) Prognostic value of epidermal growth factor-receptor, T138 and T43 expression in bladder cancer. Br J Cancer 71(1):196–200

    PubMed  CAS  Google Scholar 

  8. Lipponen P, Eskelinen M (1994) Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer 69(6):1120–1125

    PubMed  CAS  Google Scholar 

  9. Liukkonen T, Rajala P, Raitanen M, Rintala E, Kaasinen E, Lipponen P (1999) Prognostic value of MIB-1 score, p53, EGFr, mitotic index and papillary status in primary superficial (Stage pTa/T1) bladder cancer: a prospective comparative study. Eur Urol 36(5):393–400. doi:10.1159/000020039

    Article  PubMed  CAS  Google Scholar 

  10. Kramer C, Klasmeyer K, Bojar H, Schulz WA, Ackermann R, Grimm MO (2007) Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome. Cancer 109(10):2016–2024. doi:10.1002/cncr.22627

    Article  PubMed  CAS  Google Scholar 

  11. Kruger S, Weitsch G, Buttner H, Matthiensen A, Bohmer T, Marquardt T et al (2002) Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome. Int J Oncol 21(5):981–987

    PubMed  Google Scholar 

  12. Kruger S, Weitsch G, Buttner H, Matthiensen A, Bohmer T, Marquardt T et al (2002) HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: Prognostic implications. Int J Cancer 102(5):514–518. doi:10.1002/ijc.10731

    Article  PubMed  CAS  Google Scholar 

  13. Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS (2001) Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 7(7):1957–1962

    PubMed  CAS  Google Scholar 

  14. Memon AA, Sorensen BS, Meldgaard P, Fokdal L, Thykjaer T, Nexo E (2006) The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Br J Cancer 94(11):1703–1709

    PubMed  CAS  Google Scholar 

  15. Xia G, Kumar SR, Hawes D, Cai J, Hassanieh L, Groshen S et al (2006) Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer. J Urol 175(4):1245–1252. doi:10.1016/S0022-5347(05)00736-6

    Article  PubMed  CAS  Google Scholar 

  16. Mitra AP, Almal AA, George B, Fry DW, Lenehan PF, Pagliarulo V et al (2006) The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer. BMC Cancer 6:159. doi:10.1186/1471-2407-6-159

    Article  PubMed  CAS  Google Scholar 

  17. Mitra AP, Cote RJ (2009) Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol 3:251–285. doi:10.1146/annurev.pathol.4.110807.092230

    Google Scholar 

  18. Fitzgerald JM, Ramchurren N, Rieger K, Levesque P, Silverman M, Libertino JA et al (1995) Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. J Natl Cancer Inst 87(2):129–133. doi:10.1093/jnci/87.2.129

    Article  PubMed  CAS  Google Scholar 

  19. Birkhahn M, Williams AJ, Mitra AP, Lam G, Steven KE, Ye W et al (2008) Molecular markers for tumor recurrence and progression in low and high grade pTa bladder cancer. AACR Annual Meeting; San Diego, CA. American Association for Cancer Research

  20. Dunn KL, Espino PS, Drobic B, He S, Davie JR (2005) The Ras–MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem Cell Biol 83(1):1–14. doi:10.1139/o04-121

    Article  PubMed  CAS  Google Scholar 

  21. Hipfner DR, Cohen SM (2004) Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol 5(10):805–815. doi:10.1038/nrm1491

    Article  PubMed  CAS  Google Scholar 

  22. Lipponen PK (1995) Expression of c-myc protein is related to cell proliferation and expression of growth factor receptors in transitional cell bladder cancer. J Pathol 175(2):203–210. doi:10.1002/path.1711750208

    Article  PubMed  CAS  Google Scholar 

  23. Zaharieva B, Simon R, Ruiz C, Oeggerli M, Mihatsch MJ, Gasser T et al (2005) High-throughput tissue microarray analysis of CMYC amplification in urinary bladder cancer. Int J Cancer 117(6):952–956. doi:10.1002/ijc.21253

    Article  PubMed  CAS  Google Scholar 

  24. Sears RC, Nevins JR (2002) Signaling networks that link cell proliferation and cell fate. J Biol Chem 277(14):11617–11620. doi:10.1074/jbc.R100063200

    Article  PubMed  CAS  Google Scholar 

  25. Kerkhoff E, Rapp UR (1998) Cell cycle targets of Ras/Raf signalling. Oncogene 17(11 Reviews):1457–1462

    Article  PubMed  CAS  Google Scholar 

  26. Mitra AP, Lin H, Cote RJ, Datar RH (2005) Biomarker profiling for cancer diagnosis, prognosis and therapeutic management. Natl Med J India 18(6):304–312

    PubMed  Google Scholar 

  27. Johnson M, Toms S (2005) Mitogenic signal transduction pathways in meningiomas: novel targets for meningioma chemotherapy? J Neuropathol Exp Neurol 64(12):1029–1036. doi:10.1097/01.jnen.0000189834.63951.81

    Article  PubMed  CAS  Google Scholar 

  28. Langzam L, Koren R, Gal R, Kugel V, Paz A, Farkas A et al (2001) Patterns of protein kinase C isoenzyme expression in transitional cell carcinoma of bladder: relation to degree of malignancy. Am J Clin Pathol 116(3):377–385. doi:10.1309/1VKK-HWH7-YVJN-7UF7

    Article  PubMed  CAS  Google Scholar 

  29. Varga A, Czifra G, Tallai B, Nemeth T, Kovacs I, Kovacs L et al (2004) Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas. Eur Urol 46(4):462–465

    PubMed  CAS  Google Scholar 

  30. Kong C, Zhu Y, Liu D, Yu M, Li S, Li Z et al (2005) Role of protein kinase C-alpha in superficial bladder carcinoma recurrence. Urology 65(6):1228–1232. doi:10.1016/j.urology.2005.01.007

    Article  PubMed  Google Scholar 

  31. Mitra AP, Lin H, Datar RH, Cote RJ (2006) Molecular biology of bladder cancer: Prognostic and clinical implications. Clin Genitourin Cancer 5(1):67–77. doi:10.3816/CGC.2006.n.020

    Article  PubMed  CAS  Google Scholar 

  32. Mitra AP, Datar RH, Cote RJ (2005) Molecular staging of bladder cancer. BJU Int 96(1):7–12. doi:10.1111/j.1464-410X.2005.05557.x

    Article  PubMed  CAS  Google Scholar 

  33. Esrig D, Spruck CHIII, Nichols PW, Chaiwun B, Steven K, Groshen S et al (1993) p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 143(5):1389–1397

    PubMed  CAS  Google Scholar 

  34. Cordon-Cardo C, Dalbagni G, Saez GT, Oliva MR, Zhang ZF, Rosai J et al (1994) p53 mutations in human bladder cancer: genotypic versus phenotypic patterns. Int J Cancer 56(3):347–353. doi:10.1002/ijc.2910560309

    Article  PubMed  CAS  Google Scholar 

  35. Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC et al (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331(19):1259–1264. doi:10.1056/NEJM199411103311903

    Article  PubMed  CAS  Google Scholar 

  36. Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld J, Fair WR et al (1993) Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85(1):53–59. doi:10.1093/jnci/85.1.53

    Article  PubMed  CAS  Google Scholar 

  37. Serth J, Kuczyk MA, Bokemeyer C, Hervatin C, Nafe R, Tan HK et al (1995) p53 immunohistochemistry as an independent prognostic factor for superficial transitional cell carcinoma of the bladder. Br J Cancer 71(1):201–205

    PubMed  CAS  Google Scholar 

  38. George B, Datar RH, Wu L, Cai J, Patten N, Beil SJ et al (2007) p53 gene and protein status: The role of p53 alterations in predicting outcome in patients with bladder cancer. J Clin Oncol 25(34):5352–5358. doi:10.1200/JCO.2006.10.4125

    Article  PubMed  CAS  Google Scholar 

  39. Mitra AP, Birkhahn M, Cote RJ (2007) p53 and retinoblastoma pathways in bladder cancer. World J Urol 25(6):563–571. doi:10.1007/s00345-007-0197-0

    Article  PubMed  CAS  Google Scholar 

  40. Stein JP, Ginsberg DA, Grossfeld GD, Chatterjee SJ, Esrig D, Dickinson MG et al (1998) Effect of p21 WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90(14):1072–1079. doi:10.1093/jnci/90.14.1072

    Article  PubMed  CAS  Google Scholar 

  41. Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7(7A):1126–1132. doi:10.1101/gad.7.7a.1126

    Article  PubMed  CAS  Google Scholar 

  42. Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92(6):725–734. doi:10.1016/S0092-8674(00)81401-4

    Article  PubMed  CAS  Google Scholar 

  43. Birkhahn M, Mitra AP, Cote RJ (2007) Molecular markers for bladder cancer: the road to a multimarker approach. Expert Rev Anticancer Ther 7(12):1717–1727. doi:10.1586/14737140.7.12.1717

    Article  PubMed  CAS  Google Scholar 

  44. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–31. doi:10.1038/nm0195-27

    Article  PubMed  CAS  Google Scholar 

  45. Folkman J, Hochberg M (1973) Self-regulation of growth in three dimensions. J Exp Med 138(4):745–753. doi:10.1084/jem.138.4.745

    Article  PubMed  CAS  Google Scholar 

  46. Folkman J (1993) Tumor angiogenesis. In: Holland JF, Frei EI, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer Medicine, 3 edn. Lea & Febiger, Philadelphia, pp 153–170

    Google Scholar 

  47. Patard JJ, Rioux-Leclercq N, Fergelot P (2006) Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 49(4):633–643. doi:10.1016/j.eururo.2006.01.016

    Article  PubMed  CAS  Google Scholar 

  48. Folkman J (1983) Angiogenesis: initiation and modulation. Symp Fundam Cancer Res 36:201–208

    PubMed  CAS  Google Scholar 

  49. Goddard JC, Sutton CD, Furness PN, O’Byrne KJ, Kockelbergh RC (2003) Microvessel density at presentation predicts subsequent muscle invasion in superficial bladder cancer. Clin Cancer Res 9(7):2583–2586

    PubMed  Google Scholar 

  50. Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG et al (1995) Angiogenesis in bladder cancer: Relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 87(21):1603–1612. doi:10.1093/jnci/87.21.1603

    Article  PubMed  CAS  Google Scholar 

  51. Canoglu A, Gogus C, Beduk Y, Orhan D, Tulunay O, Baltaci S (2004) Microvessel density as a prognostic marker in bladder carcinoma: correlation with tumor grade, stage and prognosis. Int Urol Nephrol 36(3):401–405. doi:10.1007/s11255-004-8869-9

    Article  PubMed  Google Scholar 

  52. Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GN, Harris AL (1994) Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74(6):762–766

    Article  PubMed  CAS  Google Scholar 

  53. Jaeger TM, Weidner N, Chew K, Moore DH, Kerschmann RL, Waldman FM et al (1995) Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol 154(1):69–71. doi:10.1016/S0022-5347(01)67230-6

    Article  PubMed  CAS  Google Scholar 

  54. Bochner BH, Esrig D, Groshen S, Dickinson M, Weidner N, Nichols PW et al (1997) Relationship of tumor angiogenesis and nuclear p53 accumulation in invasive bladder cancer. Clin Cancer Res 3(9):1615–1622

    PubMed  CAS  Google Scholar 

  55. Klagsbrun M, D’Amore PA (1996) Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev 7(3):259–270. doi:10.1016/S1359-6101(96)00027-5

    Article  PubMed  CAS  Google Scholar 

  56. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC et al (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266(18):11947–11954

    PubMed  CAS  Google Scholar 

  57. Crew JP, O’Brien T, Bradburn M, Fuggle S, Bicknell R, Cranston D et al (1997) Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res 57(23):5281–5285

    PubMed  CAS  Google Scholar 

  58. Yang CC, Chu KC, Yeh WM (2004) The expression of vascular endothelial growth factor in transitional cell carcinoma of urinary bladder is correlated with cancer progression. Urol Oncol 22(1):1–6. doi:10.1016/S1078-1439(03)00015-2

    PubMed  Google Scholar 

  59. Bernardini S, Fauconnet S, Chabannes E, Henry PC, Adessi G, Bittard H (2001) Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer. J Urol 166(4):1275–1279. doi:10.1016/S0022-5347(05)65752-7

    Article  PubMed  CAS  Google Scholar 

  60. Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265(5178):1582–1584. doi:10.1126/science.7521539

    Article  PubMed  CAS  Google Scholar 

  61. Grossfeld GD, Ginsberg DA, Stein JP, Bochner BH, Esrig D, Groshen S et al (1997) Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89(3):219–227. doi:10.1093/jnci/89.3.219

    Article  PubMed  CAS  Google Scholar 

  62. Lerner SP (2005) Bladder cancer clinical trials. Urol Oncol 23(4):275–279. doi:10.1016/j.urolonc.2005.05.005

    PubMed  Google Scholar 

  63. Advanced Bladder Cancer Meta-analysis Collaboration (2003) Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361(9373):1927–1934. doi:10.1016/S0140-6736(03)13580-5

    Google Scholar 

  64. Winquist E, Kirchner TS, Segal R, Chin J, Lukka H (2004) Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol 171(2 Pt 1):561–569. doi:10.1097/01.ju.0000090967.08622.33

    Article  PubMed  CAS  Google Scholar 

  65. Advanced Bladder Cancer Overview Collaboration (2005) Neoadjuvant chemotherapy for invasive bladder cancer. Cochrane Database Syst Rev 2:CD005246

    Google Scholar 

  66. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2006) Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Cochrane Database Syst Rev 2:CD006018

  67. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG (1997) p53 and treatment of bladder cancer. Nature 385(6612):123–125. doi:10.1038/385123b0

    Article  PubMed  CAS  Google Scholar 

  68. Waldman T, Lengauer C, Kinzler KW, Vogelstein B (1996) Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381(6584):713–716. doi:10.1038/381713a0

    Article  PubMed  CAS  Google Scholar 

  69. Mitra AP, Cote RJ (2007) Searching for novel therapeutics and targets: Insights from clinical trials. Urol Oncol 25(4):341–343. doi:10.1016/j.urolonc.2007.05.004

    PubMed  CAS  Google Scholar 

  70. Widakowich C, de Castro G Jr, de Azambuja E, Dinh P, Awada A (2007) Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist 12(12):1443–1455. doi:10.1634/theoncologist.12-12-1443

    Article  PubMed  CAS  Google Scholar 

  71. Rocha-Lima CM, Soares HP, Raez LE, Singal R (2007) EGFR targeting of solid tumors. Cancer Control 14(3):295–304

    PubMed  Google Scholar 

  72. Homsi J, Daud AI (2007) Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control 14(3):285–294

    PubMed  Google Scholar 

  73. Zureikat AH, McKee MD (2008) Targeted therapy for solid tumors: current status. Surg Oncol Clin N Am 17(2):279–301, vii–viii. doi:10.1016/j.soc.2008.01.004

    Google Scholar 

  74. Nutt JE, Lazarowicz HP, Mellon JK, Lunec J (2004) Gefitinib (‘Iressa’, ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2. Br J Cancer 90(8):1679–1685. doi:10.1038/sj.bjc.6601768

    Article  PubMed  CAS  Google Scholar 

  75. Dominguez-Escrig JL, Kelly JD, Neal DE, King SM, Davies BR (2004) Evaluation of the therapeutic potential of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in preclinical models of bladder cancer. Clin Cancer Res 10(14):4874–4884. doi:10.1158/1078-0432.CCR-04-0034

    Article  PubMed  CAS  Google Scholar 

  76. Shrader M, Pino MS, Lashinger L, Bar-Eli M, Adam L, Dinney CP et al (2007) Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKT-mediated X-linked inhibitor of apoptosis protein expression. Cancer Res 67(4):1430–1435. doi:10.1158/0008-5472.CAN-06-1224

    Article  PubMed  CAS  Google Scholar 

  77. Nutt JE, Foster PA, Mellon JK, Lunec J (2007) hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours. Br J Cancer 96(5):762–768. doi:10.1038/sj.bjc.6603620

    Article  PubMed  CAS  Google Scholar 

  78. Villares GJ, Zigler M, Blehm K, Bogdan C, McConkey D, Colin D et al (2007) Targeting EGFR in bladder cancer. World J Urol 25(6):573–579. doi:10.1007/s00345-007-0202-7

    Article  PubMed  CAS  Google Scholar 

  79. Kassouf W, Brown GA, Black PC, Fisher MB, Inamoto T, Luongo T et al (2008) Is vascular endothelial growth factor modulation a predictor of the therapeutic efficacy of gefitinib for bladder cancer? J Urol 180(3):1146–1153. doi:10.1016/j.juro.2008.05.001

    Article  PubMed  CAS  Google Scholar 

  80. Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S et al (2000) Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6(5):2053–2063

    PubMed  CAS  Google Scholar 

  81. Philips G, Sanford B, Halabi S, Bajorin D, Small EJ (2006) Phase II study of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial carcinoma (UC): Analysis of the second cohort of CALGB 90102. ASCO Annual Meeting; Atlanta, GA. American Society of Clinical Oncology

  82. Clinical trials. National Institutes of Health; [cited 2008 October]; Available from: http://www.clinicaltrials.gov/

  83. Gallagher DJ, Milowsky MI, Bajorin DF (2008) Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting. Cancer 113(6):1284–1293. doi:10.1002/cncr.23692

    Article  PubMed  CAS  Google Scholar 

  84. Lindsey H (2006) Bevacizumab and erlotinib show promise for kidney cancer. Lancet Oncol 7(1):15. doi:10.1016/S1470-2045(05)70521-0

    Article  PubMed  Google Scholar 

  85. Huang SM, Harari PM (1999) Epidermal growth factor receptor inhibition in cancer therapy: Biology, rationale and preliminary clinical results. Invest New Drugs 17(3):259–269. doi:10.1023/A:1006384521198

    Article  PubMed  CAS  Google Scholar 

  86. Mellstedt H (2003) Monoclonal antibodies in human cancer. Drugs Today (Barc) 39(Suppl C):1–16

    CAS  Google Scholar 

  87. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ et al (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5(2):257–265

    PubMed  CAS  Google Scholar 

  88. Inoue K, Slaton JW, Perrotte P, Davis DW, Bruns CJ, Hicklin DJ 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. Clin Cancer Res 6(12):4874–4884

    PubMed  CAS  Google Scholar 

  89. Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr 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. J Clin Oncol 25(16):2218–2224. doi:10.1200/JCO.2006.08.0994

    Article  PubMed  CAS  Google Scholar 

  90. Nelson MH, Dolder CR (2006) Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother 40(2):261–269. doi:10.1345/aph.1G387

    Article  PubMed  CAS  Google Scholar 

  91. McHugh LA, Kriajevska M, Mellon JK, Griffiths TR (2007) Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens—evidence of schedule-dependent synergy. Urology 69(2):390–394. doi:10.1016/j.urology.2006.12.003

    Article  PubMed  Google Scholar 

  92. Wulfung C, Machiels JP, Richel DJ, Grimm MO, Treiber U, De Groot MR et al (2005) EGF20003: a single-arm, multicentre, open-label phase II study of orally administered lapatinib (GW572016) as single-agent, second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: final analysis. Ann Oncol 15(suppl 3):4160

    Google Scholar 

  93. Adnane L, Trail PA, Taylor I, Wilhelm SM (2006) Sorafenib (BAY 43–9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 407:597–612. doi:10.1016/S0076-6879(05)07047-3

    Article  PubMed  CAS  Google Scholar 

  94. Gallagher DJ, Milowsky MI, Gerst SR, Iasonos A, Riches J, Boyle MG et al (2007) Phase II study of sunitinib in patients (pts) with relapsed or refractory urothelial carcinoma (UC). ASCO Annual Meeting; Chicago, IL. American Society of Clinical Oncology

  95. Bradley DA, Dunn R, Nanus D, Stadler W, Dreicer R, Rosenberg J et al (2007) Randomized, double-blind, placebo-controlled phase II trial of maintenance sunitinib versus placebo after chemotherapy for patients with advanced urothelial carcinoma: scientific rationale and study design. Clin Genitourin Cancer 5(7):460–463. doi:10.3816/CGC.2007.n.037

    Article  PubMed  CAS  Google Scholar 

  96. Pagliaro LC (2000) Gene therapy for bladder cancer. World J Urol 18(2):148–151. doi:10.1007/s003450050188

    Article  PubMed  CAS  Google Scholar 

  97. Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P et al (2003) Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: A phase I study of p53 gene therapy. J Clin Oncol 21(12):2247–2253. doi:10.1200/JCO.2003.09.138

    Article  PubMed  CAS  Google Scholar 

  98. Kuball J, Wen SF, Leissner J, Atkins D, Meinhardt P, Quijano E et al (2002) Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 20(4):957–965. doi:10.1200/JCO.20.4.957

    Article  PubMed  CAS  Google Scholar 

  99. Pagliaro LC, Keyhani A, Liu B, Perrotte P, Wilson D, Dinney CP (2003) Adenoviral p53 gene transfer in human bladder cancer cell lines: cytotoxicity and synergy with cisplatin. Urol Oncol 21(6):456–462. doi:10.1016/S1078-1439(03)00032-2

    PubMed  CAS  Google Scholar 

  100. Loskog A, Hedlund T, Wester K, de la Torre M, Philipson L, Malmstrom PU et al (2002) Human urinary bladder carcinomas express adenovirus attachment and internalization receptors. Gene Ther 9(9):547–553. doi:10.1038/sj.gt.3301689

    Article  PubMed  CAS  Google Scholar 

  101. Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowsky AI, Tseng CP et al (1999) Loss of adenoviral receptor expression in human bladder cancer cells: A potential impact on the efficacy of gene therapy. Cancer Res 59(2):325–330

    PubMed  CAS  Google Scholar 

  102. Sachs MD, Ramamurthy M, Poel H, Wickham TJ, Lamfers M, Gerritsen W et al (2004) Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Cancer Gene Ther 11(7):477–486. doi:10.1038/sj.cgt.7700726

    Article  PubMed  CAS  Google Scholar 

  103. Osai WE, Ng CS, Pagliaro LC (2008) Positive response to bevacizumab in a patient with metastatic, chemotherapy-refractory urothelial carcinoma. Anticancer Drugs 19(4):427–429

    Article  PubMed  CAS  Google Scholar 

  104. Sakamoto S, Ryan AJ, Kyprianou N (2008) Targeting vasculature in urologic tumors: mechanistic and therapeutic significance. J Cell Biochem 103(3):691–708. doi:10.1002/jcb.21442

    Article  PubMed  CAS  Google Scholar 

  105. Azad NS, Posadas EM, Kwitkowski VE, Steinberg SM, Jain L, Annunziata CM et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26(22):3709–3714. doi:10.1200/JCO.2007.10.8332

    Article  PubMed  CAS  Google Scholar 

  106. Dupont J, Bienvenu B, Aghajanian C, Pezzulli S, Sabbatini P, Vongphrachanh P et al (2004) Phase I and pharmacokinetic study of the novel oral cell-cycle inhibitor Ro 31-7453 in patients with advanced solid tumors. J Clin Oncol 22(16):3366–3374. doi:10.1200/JCO.2004.12.007

    Article  PubMed  CAS  Google Scholar 

  107. Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS et al (2002) Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci USA 99(17):11399–11404. doi:10.1073/pnas.172398399

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest statement

The authors are not aware of any conflicts of interest that might be perceived as affecting the objectivity of this paper.

Author information

Authors and Affiliations

  1. Departments of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA

    Ramy F. Youssef, Anirban P. Mitra, Georg Bartsch Jr & Richard J. Cote

  2. Departments of Urology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA

    Ramy F. Youssef, Georg Bartsch Jr, Peter A. Jones, Donald G. Skinner & Richard J. Cote

  3. Departments of Biochemistry and Molecular Biology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    Peter A. Jones

  4. Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

    Ramy F. Youssef

  5. Department of Urology, Ulm University, Ulm, Germany

    Georg Bartsch Jr

Authors
  1. Ramy F. Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anirban P. Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg Bartsch Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter A. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald G. Skinner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard J. Cote
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. Cote.

Additional information

R. F. Youssef, A. P. Mitra, G. Bartsch Jr have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Youssef, R.F., Mitra, A.P., Bartsch, G. et al. Molecular targets and targeted therapies in bladder cancer management. World J Urol 27, 9–20 (2009). https://doi.org/10.1007/s00345-008-0357-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-008-0357-x

Keywords

Search

Navigation