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Potential Molecular Targets: From Bench to Bedside

  • Ajay Matta
  • Ranju Ralhan
Part of the Head and Neck Cancer Clinics book series (HNCC)

Abstract

The 5-year survival rates of patients with head and neck squamous cell carcinoma (HNSCC) (~50 % at 5 years) have not improved significantly despite advances in multimodality therapy, including surgery, radiation and chemotherapy. The current treatment strategies of chemotherapy (CT) and radiation therapy (RT), which have been used routinely for the management of head and neck cancer (HNC), are deficient in a targeted approach and result in treatment-related toxicities and relapses. Molecular-targeted therapies with inhibitors of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), either alone or in combination with conventional treatments, have shown limited improved efficacy. An in-depth understanding of the complex aberrant signalling pathways and networks in cancer has been achieved by advances in ‘omics’ and bioinformatics. The key deregulated signalling pathways in HNSCC include EGFR, Ras, tumour growth factor-beta (TGF-β), signal transducer and activator of transcription (STAT), Wnt/β-catenin and PI3-K/Akt/mTOR. The aberrant activities of these interrelated signalling pathways contribute to the development of HNSCC. Knowledge of cross-talks between these cellular pathways and their networks will form the basis of developing new strategies for targeting multiple molecular components for more effective prevention and treatment of HNSCC. Major emphasis is being laid on designing new therapeutic strategies targeting multiple signalling pathways for more effective disease management. However, extrapolating in vitro findings to patient management often poses major challenges that limit the clinical efficacy of these strategies. This chapter discusses how understanding the deregulated signalling networks can explain the pitfalls in translating the laboratory findings from bench to bedside; novel approaches to overcome these problems in HNC will be suggested.

Keywords

Vascular Endothelial Growth Factor Epithelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor Epithelial Growth Factor Receptor Inhibitor Epithelial Growth Factor Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA: A Cancer Journal for Clinicians 2010;60:277–300.Google Scholar
  2. 2.
    Lee NY, Le QT. New developments in radiation therapy for head and neck cancer: Intensity-modulated radiation therapy and hypoxia targeting. Semin Oncol 2008;35:236–50.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Guerrero Urbano T, Clark CH, Hansen VN, et al. A phase I study of dose-escalated chemoradiation with accelerated intensity modulated radiotherapy in locally advanced head and neck cancer. Radiother Oncol 2007;85:36–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Bhide S, Clark C, Harrington K, et al. Intensity modulated radiotherapy improves target coverage and parotid gland sparing when delivering total mucosal irradiation in patients with squamous cell carcinoma of head and neck of unknown primary site. Med Dosim 2007;32:188–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Miles EA, Clark CH, Urbano MT, et al. The impact of introducing intensity modulated radiotherapy into routine clinical practice. Radiother Oncol 2005;77:241–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to loco-regional treatment for head and neck squamous cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949–55.CrossRefPubMedGoogle Scholar
  7. 7.
    Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44.CrossRefPubMedGoogle Scholar
  9. 9.
    Argiris A, Karamouzis MV, Raben D, et al. Head and neck cancer. Lancet 2008;371:1695–709.CrossRefPubMedGoogle Scholar
  10. 10.
    Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Dirix P, Nuyts S. Evidence-based organ-sparing radiotherapy in head and neck cancer. Lancet Oncol 2010;11:85–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Budach W, Hehr T, Budach V, et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 2006;6:28.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Gibson MK, Li Y, Murphy B, et al. Eastern Cooperative Oncology Group, Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:3562–7.CrossRefPubMedGoogle Scholar
  14. 14.
    de Castro G Jr, Snitcovsky IM, Gebrim EM, et al. High-dose cisplatin concurrent to conventionally delivered radiotherapy is associated with unacceptable toxicity in unresectable, non-metastatic stage IV head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 2007;264:1475–82.Google Scholar
  15. 15.
    Singh B. Molecular pathogenesis of head and neck cancers. J Surg Oncol 2008;97:634–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Molinolo AA, Amornphimoltham P, Squarize CH, et al. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol 2009;45:324–34.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Warnakulasuriya KA, Ralhan R. Clinical, pathological, cellular and molecular lesions caused by oral smokeless tobacco—a review. J Oral Pathol Med 2007;36:63–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Arredondo J, Chernyavsky AI, Jolkovsky DL, et al. Receptor-mediated tobacco toxicity: Cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J 2006;20:2093–101.CrossRefPubMedGoogle Scholar
  19. 19.
    Neiva KG, Zhang Z, Miyazawa M, et al. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 2009;11:583–93.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Chen CC, Chen WC, Lu CH, et al. Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor. Int J Radiat Oncol Biol Phys 2010;76:1214–24.CrossRefPubMedGoogle Scholar
  21. 21.
    Prince ME, Ailles LE. Cancer stem cells in head and neck squamous cell cancer. J Clin Oncol 2008;26:2871–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Song J, Chang I, Chen Z, et al. Characterization of side populations in HNSCC: Highly invasive, chemoresistant and abnormal Wnt signaling. PLoS One 2010;5:e11456.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Shakib K, Schrattenholz A, Soskic V. Stem cells in head and neck squamous cell carcinoma. Br J Oral Maxillofac Surg 2010 Sep 8. [Epub ahead of print].Google Scholar
  24. 24.
    Sano D, Fooshee DR, Zhao M, et al. Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model. Head Neck 13 Jul 2010. [Epub ahead of print].Google Scholar
  25. 25.
    Goerner M, Seiwert TY, Sudhoff H. Molecular targeted therapies in head and neck cancer—an update of recent developments. Head Neck Oncol 2010;2:8.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Razak AR, Siu LL, Le Tourneau C. Molecular targeted therapies in all histologies of head and neck cancers: An update. Curr Opin Oncol 2010;22:212–20.CrossRefPubMedGoogle Scholar
  27. 27.
    Bozec A, Peyrade F, Fischel JL, et al. Emerging molecular targeted therapies in the treatment of head and neck cancer. Expert Opin Emerg Drugs 2009;14:299–310.CrossRefPubMedGoogle Scholar
  28. 28.
    Dietz A, Boehm A, Mozet C, et al. Current aspects of targeted therapy in head and neck tumors. Eur Arch Otorhinolaryngol 2008;265:3–12.CrossRefGoogle Scholar
  29. 29.
    Shirai K, O’Brien PE. Molecular targets in squamous cell carcinoma of the head and neck. Curr Treat Options Oncol 2007;8:239–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Langer CJ. Targeted therapy in head and neck cancer: State-of-the-art 2007 and review of clinical applications. Cancer 2008;112:2635–45.CrossRefPubMedGoogle Scholar
  31. 31.
    Fung C, Grandis JR. Emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs 2010;15:355–73.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Cassell A, Grandis JR. Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Expert Opin Investig Drugs 2010;19:709–22.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Harrington KJ, Kazi R, Bhide SA, et al. Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents. Indian J Cancer 2010;47:248–59.CrossRefPubMedGoogle Scholar
  34. 34.
    Choong NW, Cohen EE. Epidermal growth factor receptor directed therapy in head and neck cancer. Crit Rev Oncol Hematol 2006;57:25–43.CrossRefPubMedGoogle Scholar
  35. 35.
    Harari PM, Huang S. Radiation combined with EGFR signal inhibitors: Head and neck cancer focus. Semin Radiat Oncol 2006;16:38–44.CrossRefPubMedGoogle Scholar
  36. 36.
    Moon C, Chae YK, Lee J. Targeting epidermal growth factor receptor in head and neck cancer: Lessons learned from cetuximab. Exp Biol Med (Maywood) 2010;235:907–20.CrossRefGoogle Scholar
  37. 37.
    Ang KK, Andratschke NH, Milas L. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Int J Radiat Oncol Biol Phys 2004;58:959–65.CrossRefPubMedGoogle Scholar
  38. 38.
    Rodemann HP, Dittmann K, Toulany M. Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol 2007;83:781–91.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim S, Grandis JR, Rinaldo A, et al. Emerging perspectives in epidermal growth factor receptor targeting in head and neck cancer. Head Neck 2008;30:667–74.CrossRefPubMedGoogle Scholar
  40. 40.
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78.CrossRefPubMedGoogle Scholar
  41. 41.
    Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Teoh DC, Rodger S, Say J, et al. Hypofractionated radiotherapy plus cetuximab in locally advanced head and neck cancer. Clin Oncol (R Coll Radiol) 2008;20:717.CrossRefGoogle Scholar
  43. 43.
    Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–27.CrossRefPubMedGoogle Scholar
  44. 44.
    Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006;24:72–8.Google Scholar
  45. 45.
    Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5578–87.CrossRefPubMedGoogle Scholar
  46. 46.
    Bourhis J, Rivera F, Mesia R, et al. Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2866–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Bernier J. Drug Insight: Cetuximab in the treatment of recurrent and metastatic squamous cell carcinoma of the head and neck. Nat Clin Pract Oncol 2008;5:705–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646–54.CrossRefPubMedGoogle Scholar
  49. 49.
    Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5568–77.CrossRefPubMedGoogle Scholar
  50. 50.
    Mesia R, Rivera F, Kawecki A, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010. [Epub ahead of print].Google Scholar
  51. 51.
    Rowan K. Should cetuximab replace cisplatin in head and neck cancer? J Natl Cancer Inst 2010;102:74–6, 8.CrossRefPubMedGoogle Scholar
  52. 52.
    Rogers SJ, Harrington KJ, Rhys-Evans P, et al. Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev 2005;24:47–69.CrossRefPubMedGoogle Scholar
  53. 53.
    Morgillo F, Bareschino MA, Bianco R, et al. Primary and acquired resistance to anti-EGFR targeted drugs in cancer therapy. Differentiation 2007;75:788–99.CrossRefPubMedGoogle Scholar
  54. 54.
    Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 2006;12:5064–73.CrossRefPubMedGoogle Scholar
  55. 55.
    Erjala K, Sundvall M, Junttila TT, et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res 2006;12:4103–11.CrossRefPubMedGoogle Scholar
  56. 56.
    Saltz L, Easley C, Kirkpatrick P. Panitumumab. Nat Rev Drug Discov 2006;5:987–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Kim R. Cetuximab and panitumumab: Are they interchangeable? Lancet Oncol 2009;10:1140–1.CrossRefPubMedGoogle Scholar
  58. 58.
    Guglin M, Cutro R, Mishkin JD. Trastuzumab-induced cardiomyopathy. J Card Fail 2008;14:437–44.CrossRefPubMedGoogle Scholar
  59. 59.
    Rivera F, Vega-Villegas ME, Lopez-Brea MF, et al. Current situation of Panitumumab, Matuzumab, Nimotuzumab and Zalutumumab. Acta Oncol 2008;47:9–19.CrossRefPubMedGoogle Scholar
  60. 60.
    Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864–71.CrossRefPubMedGoogle Scholar
  61. 61.
    Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005;11:8418–24.CrossRefPubMedGoogle Scholar
  62. 62.
    Caponigro F, Romano C, Milano A, et al. A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. Anticancer Drugs 2008;19:739–44.CrossRefPubMedGoogle Scholar
  63. 63.
    Chua DT, Wei WI, Wong MP, et al. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head Neck 2008;30:863–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Hainsworth JD, Spigel DR, Burris HA III, et al. Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck. Cancer 2009;115:2138–46.CrossRefPubMedGoogle Scholar
  65. 65.
    Argiris A, Ghebremichael M, Gilbert J, et al. A phase III randomized, placebo-controlled trial of docetaxel (D) with or without gefitinib (G) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): A trial of the Eastern Cooperative Oncology Group (ECOG). J Clin Oncol 2009;27(Suppl):5 s (abstract 6011).Google Scholar
  66. 66.
    Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77–85.CrossRefPubMedGoogle Scholar
  67. 67.
    Siu LL, Soulieres D, Chen EX, et al. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 2007;25:2178–83.CrossRefPubMedGoogle Scholar
  68. 68.
    Kim ES, Kies MS, Glisson BS, et al. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25 (18S)(June 20 Supplement):6013.Google Scholar
  69. 69.
    Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Frederick BA, Helfrich BA, Coldren CD, et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 2007;6:1683–91.CrossRefPubMedGoogle Scholar
  71. 71.
    Haddad Y, Choi W, McConkey DJ. Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin Cancer Res 2009;15:532–42.PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Zandi R, Larsen AB, Andersen P, et al. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal 2007;19:2013–23.CrossRefPubMedGoogle Scholar
  73. 73.
    Schwentner I, Witsch-Baumgartner M, Sprinzl GM, et al. Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck. Head Neck 2008;30:1040–4.CrossRefPubMedGoogle Scholar
  74. 74.
    Egloff AM, Grandis JR. Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Semin Oncol 2008;35:286–97.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 2008;9:288–96.CrossRefPubMedGoogle Scholar
  76. 76.
    Nathan CO, Amirghahari N, Rong X, et al. Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. Cancer Res 2007;67:2160–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Oh SH, Kim WY, Kim JH, et al. Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma. Clin Cancer Res 2006;12:653–61.CrossRefPubMedGoogle Scholar
  78. 78.
    Jimeno A, Kulesza P, Wheelhouse J, et al. Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br J Cancer 2007;96:952–9.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Shang ZJ, Li ZB, Li JR. VEGF is up-regulated by hypoxic stimulation and related to tumour angiogenesis and severity of disease in oral squamous cell carcinoma: In vitro and in vivo studies. Int J Oral Maxillofac Surg 2006;35:533–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Liang X, Yang D, Hu J, et al. Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma. Anticancer Res 2008;28:1659–66.PubMedGoogle Scholar
  81. 81.
    Van Meter ME, Kim ES. Bevacizumab: Current updates in treatment. Curr Opin Oncol 2010 Sep 1. [Epub ahead of print].Google Scholar
  82. 82.
    Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol 2008;35:274–85.CrossRefPubMedGoogle Scholar
  83. 83.
    Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 2004;9 (Suppl 1):2–10.CrossRefPubMedGoogle Scholar
  84. 84.
    Cohen EE, Davis DW, Karrison TG, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A phase I/II study. Lancet Oncol 2009;10:247–57.PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Fujita K, Sano D, Kimura M, et al. Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma. Oncol Rep 2007;18:47–51.PubMedGoogle Scholar
  86. 86.
    Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol 2007;25:3766–73.CrossRefPubMedGoogle Scholar
  87. 87.
    Sano D, Kawakami M, Fujita K, et al. Anti-tumor effects of ZD6474 on head and neck squamous cell carcinoma. Oncol Rep 2007;17:289–95.PubMedGoogle Scholar
  88. 88.
    Gustafson DL, Frederick B, Merz AL, et al. Dose scheduling of the dual VEGFR and EGFR tyrosine kinase inhibitor vandetanib (ZD6474, Zactima) in combination with radiotherapy in EGFR-positive and EGFR-null human head and neck tumor xenografts. Cancer Chemother Pharmacol 2008;61:179–88.CrossRefPubMedGoogle Scholar
  89. 89.
    Johnson FM, Saigal B, Talpaz M, et al. Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res 2005;11:6924–32.CrossRefPubMedGoogle Scholar
  90. 90.
    Carducci MA, Musib L, Kies MS, et al. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 2006;24:4092–9.CrossRefPubMedGoogle Scholar
  91. 91.
    Specenier PM, Ciuleanu T, Latz JE, et al. Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients. Cancer Chemother Pharmacol 2009;64:233–41.CrossRefPubMedGoogle Scholar
  92. 92.
    Mazumdar A, Henderson YC, El-Naggar AK, et al. Aurora kinase A inhibition and paclitaxel as targeted combination therapy for head and neck squamous cell carcinoma. Head Neck 2009;31:625–34.PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Hao Y, Xie T, Korotcov A, et al. Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivo via cyclooxygenase-2 and apoptotic pathways. Int J Cancer 2009;124:2200–9.PubMedCentralCrossRefPubMedGoogle Scholar
  94. 94.
    Allen C, Saigal K, Nottingham L, et al. Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-{kappa}B subunits in head and neck cancer. Clin Cancer Res 2008;14:4175–85.CrossRefPubMedGoogle Scholar
  95. 95.
    Chen Z, Ricker JL, Malhotra PS, et al. Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-kappa B and activator protein-1 related mechanisms. Mol Cancer Ther 2008;7:1949–60.PubMedCentralCrossRefPubMedGoogle Scholar
  96. 96.
    Li C, Li R, Grandis JR, et al. Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells. Mol Cancer Ther 2008;7:1647–55.PubMedCentralCrossRefPubMedGoogle Scholar
  97. 97.
    Wagenblast J, Baghi M, Arnoldner C, et al. Effect of bortezomib and cetuximab in EGF-stimulated HNSCC. Anticancer Res 2008;28:2239–43.PubMedGoogle Scholar
  98. 98.
    Gillenwater AM, Zhong M, Lotan R. Histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondrial and Fas (Cd95) signaling in head and neck squamous carcinoma cells. Mol Cancer Ther 2007;6:2967–75.CrossRefPubMedGoogle Scholar
  99. 99.
    Boehm AL, Sen M, Seethala R, et al. Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck. Mol Pharmacol 2008;73:1632–42.PubMedCentralCrossRefPubMedGoogle Scholar
  100. 100.
    Xi S, Gooding WE, Grandis JR. In vivo anti-tumor efficacy of STAT3 blockade using a transcription factor decoy approach: Implications for cancer therapy. Oncogene 2005;24:970–9.CrossRefPubMedGoogle Scholar
  101. 101.
    Leong PL, Andrews GA, Johnson DE, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA 2003;100:4138–43.PubMedCentralCrossRefPubMedGoogle Scholar
  102. 102.
    Herrero R, Castellsagué X, Pawlita M, et al. IARC Multicenter Oral Cancer Study Group. J Natl Cancer Inst 2003;95:1772–83.CrossRefPubMedGoogle Scholar
  103. 103.
    Lo WY, Lai CC, Hua CH, et al. S100A8 is identified as a biomarker of HPV18-infected oral squamous cell carcinomas by suppression subtraction hybridization, clinical proteomics analysis, and immunohistochemistry staining. J Proteome Res 2007;6:2143–51.CrossRefPubMedGoogle Scholar

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© The Author(s) 2012

Authors and Affiliations

  1. 1.Department of Chemistry and Centre for Research in Mass SpectrometryYork UniversityTorontoCanada
  2. 2.Department of Otolaryngology – Head and Neck SurgeryUniversity of Toronto and Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai HospitalTorontoCanada

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