Skip to main content

Advertisement

Log in

Targeting Signaling Transduction Pathways in Bladder Cancer

  • Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Systemic therapy for urothelial carcinoma (UC) of the bladder has largely revolved around cytotoxic chemotherapy regimens. However, several recent clinical trials have explored the roles of targeted therapies which specifically inhibit signal transduction pathways. Simultaneously, a rationale for such therapies has come to the forefront of management of this disease because an overabundance of signaling pathways are genetically deranged as a result of point mutation or copy number alteration (CNA) as identified by several recent next generation sequencing (NGS) studies. Importantly, these derangements are found in all stages of disease, and therefore targeted therapies hold promise as a next step in the evolution of the medical management of both localized and metastatic UCC. We review the rationale for and progress in studying inhibition of signal transduction as a means of treatment of UCC.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Abdollah F, Gandaglia G, Thuret R, Schmitges J, Tian Z, Jeldres C, et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 2013;37(3):219–25. doi:10.1016/j.canep.2013.02.002.

    Article  PubMed  Google Scholar 

  2. Nordentoft I, Lamy P, Birkenkamp-Demtroder K, Shumansky K, Vang S, Hornshoj H, et al. Mutational context and diverse clonal development in early and late bladder cancer. Cell Rep. 2014;7(5):1649–63. doi:10.1016/j.celrep.2014.04.038.

    Article  CAS  PubMed  Google Scholar 

  3. Li Y, Xu X, Song L, Hou Y, Li Z, Tsang S, et al. Single-cell sequencing analysis characterizes common and cell-lineage-specific mutations in a muscle-invasive bladder cancer. Gigascience. 2012;1(1):12. doi:10.1186/2047-217X-1-12.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013;31(25):3133–40. doi:10.1200/JCO.2012.46.5740.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet. 2013;45(12):1459–63. doi:10.1038/ng.2798.

    Article  CAS  PubMed  Google Scholar 

  6. Balbas-Martinez C, Sagrera A, Carrillo-de-Santa-Pau E, Earl J, Marquez M, Vazquez M, et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat Genet. 2013;45(12):1464–9. doi:10.1038/ng.2799.

    Article  CAS  PubMed  Google Scholar 

  7. Solomon DA, Kim JS, Bondaruk J, Shariat SF, Wang ZF, Elkahloun AG, et al. Frequent truncating mutations of STAG2 in bladder cancer. Nat Genet. 2013;45(12):1428–30. doi:10.1038/ng.2800.

    Article  CAS  PubMed  Google Scholar 

  8. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011;43(9):875–8. doi:10.1038/ng.907.

    Article  CAS  PubMed  Google Scholar 

  9. Cancer Genome Atlas Research N. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22. doi:10.1038/nature12965. The work of The Cancer Genome Atlas research network used solely muscle-invasive bladder cancer (MIBC) specimens to identify frequently mutated genes, some previously identified but also several new targets. These MIBC tumors are the most likely to metastasize or cause death, thus the genetics identified in this manuscript serve as a basis for further research to design new detection, prognostic, predictive, and treatment algorithms. Importantly, many of these targets have drugs in the research pipeline.

    Article  Google Scholar 

  10. Nickerson ML, Dancik GM, Im KM, Edwards MG, Turan S, Brown J, et al. Concurrent alterations in TERT, KDM6A, and the BRCA Pathway in bladder cancer. Clin Cancer Res. 2014;20(18):4935–48. doi:10.1158/1078-0432.CCR-14-0330.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.

    Article  CAS  PubMed  Google Scholar 

  12. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038–42. doi:10.1056/NEJM200104053441402.

    Article  CAS  PubMed  Google Scholar 

  13. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92. doi:10.1056/NEJM200103153441101.

    Article  CAS  PubMed  Google Scholar 

  14. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39. doi:10.1056/NEJMoa040938.

    Article  CAS  PubMed  Google Scholar 

  15. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958–67. doi:10.1056/NEJMoa0904554.

    Article  CAS  PubMed  Google Scholar 

  16. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. doi:10.1126/science.1099314.

    Article  CAS  PubMed  Google Scholar 

  17. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221. doi:10.1126/science.1226344.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 2014;371(15):1426–33. doi:10.1056/NEJMoa1403352.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94–109. doi:10.1158/2159-8290.CD-13-0617.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003;13(15):1259–68.

    Article  CAS  PubMed  Google Scholar 

  21. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem. 2002;277(34):30958–67. doi:10.1074/jbc.M202678200.

    Article  CAS  PubMed  Google Scholar 

  22. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002;99(21):13571–6. doi:10.1073/pnas.202476899.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Ghosh AP, Marshall CB, Coric T, Shim EH, Kirkman R, Ballestas ME, et al. Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget. 2015;6(20):17895–910.

    Article  PubMed  Google Scholar 

  24. Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem. 1995;270(46):27531–7.

    Article  CAS  PubMed  Google Scholar 

  25. Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014;4(5):546–53. doi:10.1158/2159-8290.CD-13-0353. Many markers of sensitivity to cytotoxic or targeted chemotherapies have been identified but few have rigorously been tested to associate a mechanism. Although the authors did not show the specific mechanism of sensitivity, they did identify mutations of mTOR pathway components which might be predicted to cause sensitivity. The clinching finding was that a once-responsive tumor likely became resistant to mTOR-directed therapy when the tumor acquired a mutation the mTOR kinase itself which abrogates drug binding.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Kim PH, Cha EK, Sfakianos JP, Iyer G, Zabor EC, Scott SN, et al. Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol. 2015;67(2):198–201. doi:10.1016/j.eururo.2014.06.050.

    Article  PubMed  Google Scholar 

  27. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1. doi:10.1126/scisignal.2004088.

    Article  Google Scholar 

  28. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. doi:10.1158/2159-8290.CD-12-0095.

  29. Lamont FR, Tomlinson DC, Cooper PA, Shnyder SD, Chester JD, Knowles MA. Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br J Cancer. 2011;104(1):75–82. doi:10.1038/sj.bjc.6606016.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999;23(1):18–20. doi:10.1038/12615.

    Article  CAS  PubMed  Google Scholar 

  31. D’Avis PY, Robertson SC, Meyer AN, Bardwell WM, Webster MK, Donoghue DJ. Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ. 1998;9(1):71–8.

    PubMed  Google Scholar 

  32. Naski MC, Wang Q, Xu J, Ornitz DM. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996;13(2):233–7. doi:10.1038/ng0696-233.

    Article  CAS  PubMed  Google Scholar 

  33. Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet. 2013;22(4):795–803. doi:10.1093/hmg/dds486. This was the first report to show FGFR3 translocations occur recurrently in bladder cancer. Although rare, the mutations were only present in samples from invasive tumors. Additionally, presence of the mutation correlated with FGFR3-dependence in the presence of small molecule inhibitors and may serve as a marker to assign therapy rationally.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012;337(6099):1231–5. doi:10.1126/science.1220834.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Gil Diez de Medina S, Van Rhijn B, et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 2001;158(6):1955–9. doi:10.1016/S0002-9440(10)64665-2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Liu X, Zhang W, Geng D, He J, Zhao Y, Yu L. Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis. Genet Mol Res. 2014;13(1):1109–20. doi:10.4238/2014.February.20.12.

    Article  CAS  PubMed  Google Scholar 

  37. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65. doi:10.1016/j.ccr.2014.01.009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Al-Ahmadie HA, Iyer G, Janakiraman M, Lin O, Heguy A, Tickoo SK, et al. Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma. J Pathol. 2011;224(2):270–9. doi:10.1002/path.2892.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res. 2013;73(16):5195–205. doi:10.1158/0008-5472.CAN-12-3950.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105(7):2941–8. doi:10.1182/blood-2004-10-3913.

    Article  CAS  PubMed  Google Scholar 

  41. Milowsky MI, Dittrich C, Duran I, Jagdev S, Millard FE, Sweeney CJ, et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur J Cancer. 2014;50(18):3145–52. doi:10.1016/j.ejca.2014.10.013.

    Article  CAS  PubMed  Google Scholar 

  42. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54(20):7066–83. doi:10.1021/jm2006222.

    Article  CAS  PubMed  Google Scholar 

  43. Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, et al. Detection, characterization, and inhibition of FGFR-TACC fusions in IDH wild-type glioma. Clin Cancer Res. 2015;21(14):3307–17. doi:10.1158/1078-0432.CCR-14-2199.

    Article  PubMed  Google Scholar 

  44. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A. 2014;111(8):3110–5. doi:10.1073/pnas.1318376111. Along with #35, these two manuscripts along with that of the TCGA identified molecular subtypes of bladder cancer that are akin to the four intrinsic subtypes of breast cancer. Sensitivity to neoadjuvant chemotherapy was enriched in luminal subtypes from clinical samples. As opposed to breast cancer however which are persistent over the lifetime of the tumor, the bladder cancer subtypes seem plastic as residual cancer after neoadjuvant cisplatin-based regimens adopted a p53-like signature.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012;109(36):14476–81. doi:10.1073/pnas.1203201109.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Ross JS, Wang K, Gay LM, Al-Rohil RN, Nazeer T, Sheehan CE, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014;20(1):68–75. doi:10.1158/1078-0432.CCR-13-1992.

    Article  CAS  PubMed  Google Scholar 

  47. Willis DL, Flaig TW, Hansel DE, Milowsky MI, Grubb RL, Al-Ahmadie HA, et al. Micropapillary bladder cancer: current treatment patterns and review of the literature. Urol Oncol. 2014;32(6):826–32. doi:10.1016/j.urolonc.2014.01.020.

    Article  PubMed  Google Scholar 

  48. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224–37. doi:10.1158/2159-8290.CD-12-0349.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara Jr PN, et al. 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. 2007;25(16):2218–24. doi:10.1200/JCO.2006.08.0994.

    Article  CAS  PubMed  Google Scholar 

  50. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.

    PubMed  Google Scholar 

  51. Wong YN, Litwin S, Vaughn D, Cohen S, Plimack ER, Lee J, et al. Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. J Clin Oncol. 2012;30(28):3545–51. doi:10.1200/JCO.2012.41.9572.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Hussain M, Daignault S, Agarwal N, Grivas PD, Siefker-Radtke AO, Puzanov I, et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer. 2014;120(17):2684–93. doi:10.1002/cncr.28767.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Pruthi RS, Nielsen M, Heathcote S, Wallen EM, Rathmell WK, Godley P, et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int. 2010;106(3):349–54. doi:10.1111/j.1464-410X.2009.09101.x.

    Article  CAS  PubMed  Google Scholar 

  54. Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32(18):1889–94. doi:10.1200/JCO.2013.52.4785.

    Article  CAS  PubMed  Google Scholar 

  55. Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014;32(18):1895–901. doi:10.1200/JCO.2013.53.2465.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66. doi:10.1056/NEJMoa022148.

    Article  CAS  PubMed  Google Scholar 

  57. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. doi:10.1371/journal.pmed.0020073.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501. doi:10.1038/nature12912.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, Qin W, Fletcher CD, Vena N, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28(5):835–40. doi:10.1200/JCO.2009.25.2981.

    Article  CAS  PubMed  Google Scholar 

  60. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65(23):10992–1000. doi:10.1158/0008-5472.CAN-05-2612.

    Article  CAS  PubMed  Google Scholar 

  61. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi:10.1038/nature11412.

    Article  Google Scholar 

  62. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, et al. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009;106(40):16996–7001. doi:10.1073/pnas.0908444106.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Blair BG, Wu X, Zahari MS, Mohseni M, Cidado J, Wong HY, et al. A phosphoproteomic screen demonstrates differential dependence on HER3 for MAP kinase pathway activation by distinct PIK3CA mutations. Proteomics. 2015;15(2–3):318–26. doi:10.1002/pmic.201400342.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. 2015;33(12):1334–9. doi:10.1200/JCO.2014.55.2158.

    Article  CAS  PubMed  Google Scholar 

  65. Seront E, Rottey S, Sautois B, Kerger J, D’Hondt LA, Verschaeve V, et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Ann Oncol. 2012;23(10):2663–70. doi:10.1093/annonc/mds057.

    Article  CAS  PubMed  Google Scholar 

  66. Milowsky MI, Iyer G, Regazzi AM, Al-Ahmadie H, Gerst SR, Ostrovnaya I, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 2013;112(4):462–70. doi:10.1111/j.1464-410X.2012.11720.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Inoue K, Slaton JW, Davis DW, Hicklin DJ, McConkey DJ, Karashima T, et al. 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. Clin Cancer Res. 2000;6(7):2635–43.

    CAS  PubMed  Google Scholar 

  68. Inoue K, Slaton JW, Karashima T, Yoshikawa C, Shuin T, Sweeney P, et al. The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Clin Cancer Res. 2000;6(12):4866–73.

    CAS  PubMed  Google Scholar 

  69. Slaton JW, Millikan R, Inoue K, Karashima T, Czerniak B, Shen Y, et al. Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy. J Urol. 2004;171(2 Pt 1):570–4. doi:10.1097/01.ju.0000108845.91485.20.

    Article  CAS  PubMed  Google Scholar 

  70. Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, et al. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol. 2010;28(8):1373–9. doi:10.1200/JCO.2009.25.3922.

    Article  CAS  PubMed  Google Scholar 

  71. Grivas PD, Daignault S, Tagawa ST, Nanus DM, Stadler WM, Dreicer R, et al. Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma. Cancer. 2014;120(5):692–701. doi:10.1002/cncr.28477.

    Article  CAS  PubMed  Google Scholar 

  72. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007;6(7):2012–21. doi:10.1158/1535-7163.MCT-07-0193.

    Article  CAS  PubMed  Google Scholar 

  73. Srinivas S, Narayanan S, Harshman LC, Pachynski RK, Lam AP, Fan AC et al. Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer. Genitourinary Cancers Symposium; February 26–28; Orlando, FL. J Clin Oncol. 2015. p. Abstract #294.

  74. Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol. 2011;29(12):1525–30. doi:10.1200/JCO.2010.31.6067.

  75. Petrylak DP, Tagawa ST, Kohli M, Tang S, Zhang H, Hamid O et al. Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma. Genitourinary Cancers Symposium; February 26–28; Orlando, FL. J Clin Oncol. 2015. p. Abstract #295.

  76. Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R, et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015;33(9):1000–7. doi:10.1200/JCO.2014.58.2007.

    Article  CAS  PubMed  Google Scholar 

  77. http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. Accessed Augst 6, 2015.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Phillip H. Abbosh has received compensation from the Advanced Individual Medicine for service as a consultant.

David J. McConkey has received research funding through a grant from AstraZeneca and has been issued a patent, filed by The University of Texas M.D. Anderson Cancer Center, for the method for identifying intrinsic subtypes of muscle-invasive bladder cancer.

Elizabeth R. Plimack has received clinical trial funding through grants from Pfizer, GlaxoSmithKline, Bristol Myers-Squibb, AstraZeneca, Eli Lilly, Merck, Dendreon, and Acceleron; has received compensation from Pfizer, GlaxoSmithKline, Novartis, Genentech, Bristol Myers-Squibb, Merck, Dendreon, and Astellas for service on advisory boards; and has been issued a patent, filed by Fox Chase Cancer Center, for the methods for screening muscle-invasive bladder cancer patients for neoadjuvant chemotherapy responsiveness.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elizabeth R. Plimack.

Additional information

This article is part of the Topical Collection on Genitourinary Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abbosh, P.H., McConkey, D.J. & Plimack, E.R. Targeting Signaling Transduction Pathways in Bladder Cancer. Curr Oncol Rep 17, 58 (2015). https://doi.org/10.1007/s11912-015-0477-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-015-0477-6

Keywords

Navigation