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Targeted therapy in head and neck cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors (Cetuximab, Panitumumab, Zalutumumab), EGFR tyrosine kinase inhibitors (Gefitinib, Erloitinib), VEGFR inhibitors (Bevacizumab, Vandetanib), and various inhibitors of, e.g., Src-family kinase, PARP, proteasome, mTOR, COX, and heat shock protein. Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.

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References

  1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  3. Syrjanen S. Human papillomavirus (HPV) in head and neck cancer. J Clin Virol. 2005;32 Suppl 1:S59–66.

    Article  PubMed  CAS  Google Scholar 

  4. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94:153–6.

    Article  PubMed  CAS  Google Scholar 

  5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  6. Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer J Int Du Cancer. 2004;108:766–72.

    CAS  Google Scholar 

  7. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  8. Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol. 2004;31:744–54.

    Article  PubMed  Google Scholar 

  9. Granata R, Miceli R, Orlandi E, et al. Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study. Ann Oncol. 2011. doi:10.1093/annonc/mdr544.

  10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.

    Article  PubMed  CAS  Google Scholar 

  11. D'Souza G, Dempsey A. The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med. 2011;53 Suppl 1:S5–S11.

    Article  PubMed  Google Scholar 

  12. Sinha P, Logan HL, Mendenhall WM. Human papillomavirus, smoking, and head and neck cancer. Am J Otolaryngol. 2012;33:130–6.

    Article  PubMed  Google Scholar 

  13. Llewellyn CD, Linklater K, Bell J, Johnson NW, Warnakulasuriya S. An analysis of risk factors for oral cancer in young people: a case–control study. Oral Oncol. 2004;40:304–13.

    Article  PubMed  Google Scholar 

  14. Psyrri A, Fountzilas G. Advances in the treatment of locally advanced non-nasopharyngeal squamous cell carcinoma of the head and neck region. Med Oncol. 2006;23:1–15.

    Article  PubMed  CAS  Google Scholar 

  15. Cohen EE, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22:1743–52.

    Article  Google Scholar 

  16. Papaspyrou G, Werner JA, Dietz A. Pharmacotherapy for squamous-cell carcinoma of the head and neck. Expert Opin Pharmacother. 2011;12:397–409.

    Article  PubMed  CAS  Google Scholar 

  17. 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 Off J Am Soc Clin Oncol. 2005;23:5568–77.

    Article  CAS  Google Scholar 

  18. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol Off J Am Soc Clin Oncol. 1992;10:257–63.

    CAS  Google Scholar 

  19. Gibson MK, Li Y, Murphy B, et al. 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 Off J Am Soc Clin Oncol. 2005;23:3562–7.

    Article  CAS  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional 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.

    PubMed  CAS  Google Scholar 

  22. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091–8.

    Article  PubMed  CAS  Google Scholar 

  23. Laramore GE. Role of particle radiotherapy in the management of head and neck cancer. Curr Opin Oncol. 2009;21:224–31.

    Article  PubMed  Google Scholar 

  24. Holsinger FC. Swing of the pendulum: optimizing functional outcomes in larynx cancer. Curr Oncol Rep. 2008;10:170–5.

    Article  PubMed  Google Scholar 

  25. Lefebvre JL. Larynx preservation: the discussion is not closed. Otolaryngol Head Neck Surg: Off J Am Acad Otolaryngol-Head Neck Surg. 1998;118:389–93.

    Article  CAS  Google Scholar 

  26. Takes RP, Strojan P, Silver CE, et al. Current trends in initial management of hypopharyngeal cancer: the declining use of open surgery. Head Neck. 2012;34:270–81.

    Article  PubMed  Google Scholar 

  27. Lefebvre JL, et al. Current clinical outcomes demand new treatment options for SCCHN. Ann Oncol: Off J Eur Soc Med Oncol/ESMO. 2005;16:vi7–vi12.

    Article  Google Scholar 

  28. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol: J Eur Soc Ther Radiol Oncol. 2003;66:253–62.

    Article  Google Scholar 

  29. Tsao AS, Garden AS, Kies MS, et al. Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:4163–9.

    Article  CAS  Google Scholar 

  30. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–73.

    Article  PubMed  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Levy AR, Johnston KM, Sambrook J, et al. Indirect comparison of the efficacy of cetuximab and cisplatin in squamous cell carcinoma of the head and neck. Curr Med Res Opin. 2011;27:2253–9.

    Article  PubMed  CAS  Google Scholar 

  33. Wang CJ, Knecht R. Current concepts of organ preservation in head and neck cancer. Eur Arch Otorhinolaryngol. 2011;268:481–7.

    Article  PubMed  Google Scholar 

  34. Howard JD, Lu B, and Chung CH (2011) Therapeutic targets in head and neck squamous cell carcinoma: Identification, evaluation, and clinical translation. Oral oncology.

  35. Pryor DI, Solomon B, Porceddu SV. The emerging era of personalized therapy in squamous cell carcinoma of the head and neck. Asia Pac J Clin Oncol. 2011;7:236–51.

    Article  PubMed  Google Scholar 

  36. Segal NH, Saltz LB. Evolving treatment of advanced colon cancer. Annu Rev Med. 2009;60:207–19.

    Article  PubMed  CAS  Google Scholar 

  37. Choong NW, Cohen EE. Epidermal growth factor receptor directed therapy in head and neck cancer. Crit Rev Oncol Hematol. 2006;57:25–43.

    Article  PubMed  Google Scholar 

  38. Harari PM, Huang S. Radiation combined with EGFR signal inhibitors: head and neck cancer focus. Semin Radiat Oncol. 2006;16:38–44.

    Article  PubMed  Google Scholar 

  39. Le Tourneau C, Faivre S, Siu LL. Molecular targeted therapy of head and neck cancer: review and clinical development challenges. Eur J Cancer. 2007;43:2457–66.

    Article  PubMed  CAS  Google Scholar 

  40. Glazer CA, Chang SS, Ha PK, Califano JA. Applying the molecular biology and epigenetics of head and neck cancer in everyday clinical practice. Oral Oncol. 2009;45:440–6.

    Article  PubMed  CAS  Google Scholar 

  41. Langer CJ. Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications. Cancer. 2008;112:2635–45.

    Article  PubMed  CAS  Google Scholar 

  42. Nestor MV. Targeted radionuclide therapy in head and neck cancer. Head Neck. 2010;32:666–78.

    PubMed  Google Scholar 

  43. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53:3579–84.

    PubMed  CAS  Google Scholar 

  44. Rubin Grandis J, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284–92.

    Article  PubMed  CAS  Google Scholar 

  45. Burtness B. The role of cetuximab in the treatment of squamous cell cancer of the head and neck. Expert Opin Biol Ther. 2005;5:1085–93.

    Article  PubMed  CAS  Google Scholar 

  46. Davies RL, Grosse VA, Kucherlapati R, Bothwell M. Genetic analysis of epidermal growth factor action: assignment of human epidermal growth factor receptor gene to chromosome 7. Proc Natl Acad Sci U S A. 1980;77:4188–92.

    Article  PubMed  CAS  Google Scholar 

  47. Sato JD, Kawamoto T, Le AD, et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. 1983;1:511–29.

    PubMed  CAS  Google Scholar 

  48. Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998;37:285–9.

    Article  PubMed  CAS  Google Scholar 

  49. Lax I, Fischer R, Ng C, et al. Noncontiguous regions in the extracellular domain of EGF receptor define ligand-binding specificity. Cell Regul. 1991;2:337–45.

    PubMed  CAS  Google Scholar 

  50. Roskoski Jr R. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1–11.

    Article  PubMed  CAS  Google Scholar 

  51. Hambek M, Baghi M, Baumaun H, et al. Iressa (ZD 1839) inhibits phosphorylation of three different downstream signal transducers in head and neck cancer (SCCHN). Anticancer Res. 2005;25:1871–5.

    PubMed  CAS  Google Scholar 

  52. Haura EB, Zheng Z, Song L, Cantor A, Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:8288–94.

    Article  CAS  Google Scholar 

  53. 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 Off J Am Assoc Cancer Res. 2006;12:5064–73.

    Article  CAS  Google Scholar 

  54. Wheeler SE, Suzuki S, Thomas SM, et al. Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation. Oncogene. 2010;29:5135–45.

    Article  PubMed  CAS  Google Scholar 

  55. Udayachander M, Dean CJ, Meenakshi AN, et al. Anti-tumor activity of monoclonal antibody CIBCNSH3 generated to the human EGF receptor. Hum Antibodies. 1997;8:60–4.

    PubMed  CAS  Google Scholar 

  56. He Y, Zeng Q, Drenning SD, et al. Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter. J Natl Cancer Inst. 1998;90:1080–7.

    Article  PubMed  CAS  Google Scholar 

  57. Thomas SM, Zeng Q, Epperly MW, et al. Abrogation of head and neck squamous cell carcinoma growth by epidermal growth factor receptor ligand fused to pseudomonas exotoxin transforming growth factor alpha-PE38. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10:7079–87.

    Article  CAS  Google Scholar 

  58. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.

    Article  PubMed  CAS  Google Scholar 

  59. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:4914–21.

    Article  CAS  Google Scholar 

  60. Raben D, Bianco C, Milas L, Ang KK. Targeted therapies and radiation for the treatment of head and neck cancer: are we making progress? Semin Radiat Oncol. 2004;14:139–52.

    Article  PubMed  Google Scholar 

  61. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:2171–7.

    Article  CAS  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. Merlano M, Occelli M. Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck. Ther Clin Risk Manag. 2007;3:871–6.

    PubMed  CAS  Google Scholar 

  64. Hoang T, Huang S, Armstrong E, Eickhoff JC, Harari PM. Augmentation of radiation response with the vascular targeting agent ZD6126. Int J Radiat Oncol Biol Phys. 2006;64:1458–65.

    Article  PubMed  CAS  Google Scholar 

  65. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:1935–40.

    PubMed  CAS  Google Scholar 

  66. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2787–99.

    Article  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. Rivera F, Garcia-Castano A, Vega N, Vega-Villegas ME, Gutierrez-Sanz L. Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev Anticancer Ther. 2009;9:1421–8.

    Article  PubMed  CAS  Google Scholar 

  69. Sharafinski ME, Ferris RL, Ferrone S, Grandis JR. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck. 2010;32:1412–21.

    Article  PubMed  Google Scholar 

  70. Giusti RM, Cohen MH, Keegan P, Pazdur R. FDA review of a panitumumab (Vectibix) clinical trial for first-line treatment of metastatic colorectal cancer. Oncologist. 2009;14:284–90.

    Article  PubMed  CAS  Google Scholar 

  71. Hoy SM, Wagstaff AJ. Panitumumab: in the treatment of metastatic colorectal cancer. Drugs. 2006;66:2005–14. discussion 15–6.

    Article  PubMed  CAS  Google Scholar 

  72. Schick U, Gujral DM, Richards TM, Harrington KJ, Nutting CM. Zalutumumab in head and neck cancer. Expert Opin Biol Ther. 2012;12:119–25.

    Article  PubMed  CAS  Google Scholar 

  73. Reichert JM. Antibody-based therapeutics to watch in 2011. MAbs. 2011;3:76–99.

    Article  PubMed  Google Scholar 

  74. Capdevila J, Elez E, Macarulla T, et al. Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev. 2009;35:354–63.

    Article  PubMed  CAS  Google Scholar 

  75. Talavera A, Friemann R, Gomez-Puerta S, et al. Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. Cancer Res. 2009;69:5851–9.

    Article  PubMed  CAS  Google Scholar 

  76. Johns TG, Adams TE, Cochran JR, et al. Identification of the epitope for the epidermal growth factor receptor-specific monoclonal antibody 806 reveals that it preferentially recognizes an untethered form of the receptor. J Biol Chem. 2004;279:30375–84.

    Article  PubMed  CAS  Google Scholar 

  77. Panousis C, Rayzman VM, Johns TG, et al. Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR. Br J Cancer. 2005;92:1069–77.

    Article  PubMed  CAS  Google Scholar 

  78. Scott AM, Lee FT, Tebbutt N, et al. A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors. Proc Natl Acad Sci U S A. 2007;104:4071–6.

    Article  PubMed  CAS  Google Scholar 

  79. Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther. 1999;82:207–18.

    Article  PubMed  CAS  Google Scholar 

  80. Magne N, Fischel JL, Dubreuil A, et al. Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 (“Iressa”). Br J Cancer. 2002;86:1518–23.

    Article  PubMed  CAS  Google Scholar 

  81. Shintani S, Li C, Mihara M, et al. Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer. International Journal of Cancer. J Int Du Cancer. 2003;107:1030–7.

    Article  CAS  Google Scholar 

  82. 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 Off J Am Soc Clin Oncol. 2004;22:77–85.

    Article  CAS  Google Scholar 

  83. 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 Off J Am Soc Clin Oncol. 2003;21:1980–7.

    Article  CAS  Google Scholar 

  84. Hainsworth JD, Spigel DR, Burris 3rd HA, 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.

    Article  PubMed  CAS  Google Scholar 

  85. 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 Off J Am Soc Clin Oncol. 2009;27:1864–71.

    Article  CAS  Google Scholar 

  86. 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 Off J Am Soc Clin Oncol. 2007;25:2178–83.

    Article  CAS  Google Scholar 

  87. 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.

    Article  PubMed  CAS  Google Scholar 

  88. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6.

    Article  PubMed  CAS  Google Scholar 

  89. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–71.

    Article  PubMed  CAS  Google Scholar 

  90. Mineta H, Miura K, Ogino T, et al. Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br J Cancer. 2000;83:775–81.

    Article  PubMed  CAS  Google Scholar 

  91. Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol. 2008;35:274–85.

    Article  PubMed  Google Scholar 

  92. Miller KD. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003;3:421–2.

    Article  PubMed  CAS  Google Scholar 

  93. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427–34.

    Article  PubMed  CAS  Google Scholar 

  94. Seiwert TY, Haraf DJ, Cohen EE, et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:1732–41.

    Article  CAS  Google Scholar 

  95. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol. 2012;13:172–80.

    Google Scholar 

  96. Le QT, Raben D. Integrating biologically targeted therapy in head and neck squamous cell carcinomas. Semin Radiat Oncol. 2009;19:53–62.

    Article  PubMed  Google Scholar 

  97. Borjesson PK, Postema EJ, Roos JC, et al. Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2003;9:3961S–72S.

    Google Scholar 

  98. Ahmed S, Winter JN, Gordon LI, Evens AM. Radioimmunotherapy for the treatment of non-Hodgkin lymphoma: current status and future applications. Leuk Lymphoma. 2010;51:1163–77.

    Article  PubMed  CAS  Google Scholar 

  99. de Bree R, Kuik DJ, Quak JJ, et al. The impact of tumour volume and other characteristics on uptake of radiolabelled monoclonal antibodies in tumour tissue of head and neck cancer patients. Eur J Nucl Med. 1998;25:1562–5.

    Article  PubMed  Google Scholar 

  100. Goldenberg DM, Sharkey RM. Advances in cancer therapy with radiolabeled monoclonal antibodies. Q J Nucl Med Mol Imaging. 2006;50:248–64.

    PubMed  CAS  Google Scholar 

  101. Funaro A, Horenstein AL, Santoro P, et al. Monoclonal antibodies and therapy of human cancers. Biotechnol Adv. 2000;18:385–401.

    Article  PubMed  CAS  Google Scholar 

  102. Dunn WA, Connolly TP, Hubbard AL. Receptor-mediated endocytosis of epidermal growth factor by rat hepatocytes: receptor pathway. J Cell Biol. 1986;102:24–36.

    Article  PubMed  CAS  Google Scholar 

  103. Gladhaug IP, Refsnes M, Christoffersen T. Regulation of surface expression of high-affinity receptors for epidermal growth factor (EGF) in hepatocytes by hormones, differentiating agents, and phorbol ester. Dig Dis Sci. 1992;37:233–9.

    Article  PubMed  CAS  Google Scholar 

  104. Schechter NR, Wendt 3rd RE, Yang DJ, et al. Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. J Nucl Med. 2004;45:1683–7.

    PubMed  CAS  Google Scholar 

  105. Heider KH, Kuthan H, Stehle G, Munzert G. CD44v6: a target for antibody-based cancer therapy. Cancer Immunol Immunother. 2004;53:567–79.

    Article  PubMed  CAS  Google Scholar 

  106. Heider KH, Sproll M, Susani S, et al. Characterization of a high-affinity monoclonal antibody specific for CD44v6 as candidate for immunotherapy of squamous cell carcinomas. Cancer Immunol Immunother. 1996;43:245–53.

    Article  PubMed  CAS  Google Scholar 

  107. Heider KH, Mulder JW, Ostermann E, et al. Splice variants of the cell surface glycoprotein CD44 associated with metastatic tumour cells are expressed in normal tissues of humans and cynomolgus monkeys. Eur J Cancer. 1995;31A:2385–91.

    Article  PubMed  CAS  Google Scholar 

  108. Schrijvers AH, Quak JJ, Uyterlinde AM, et al. MAb U36, a novel monoclonal antibody successful in immunotargeting of squamous cell carcinoma of the head and neck. Cancer Res. 1993;53:4383–90.

    PubMed  CAS  Google Scholar 

  109. Brack SS, Silacci M, Birchler M, Neri D. Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:3200–8.

    Article  CAS  Google Scholar 

  110. Andratschke M, Hagedorn H, Luebbers CW, et al. Limited suitability of EpCAM for molecular staging of tumor borders in head and neck cancer. Anticancer Res. 2006;26:153–8.

    PubMed  CAS  Google Scholar 

  111. Barnes CJ, Ohshiro K, Rayala SK, El-Naggar AK, Kumar R. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13:4291–9.

    Article  CAS  Google Scholar 

  112. Sharkey RM, Blumenthal RD, Behr TM, et al. Selection of radioimmunoconjugates for the therapy of well-established or micrometastatic colon carcinoma. Int J Cancer J Int Du Cancer. 1997;72:477–85.

    CAS  Google Scholar 

  113. Koppe MJ, Postema EJ, Aarts F, et al. Antibody-guided radiation therapy of cancer. Cancer Metastasis Rev. 2005;24:539–67.

    Article  PubMed  CAS  Google Scholar 

  114. Elgqvist J. Targeted alpha therapy—part I. Curr Radiopharm. 2011;4:176.

    PubMed  CAS  Google Scholar 

  115. Colnot DR, Quak JJ, Roos JC, et al. Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck. J Nucl Med. 2000;41:1999–2010.

    PubMed  CAS  Google Scholar 

  116. Nestor M, Andersson K, Lundqvist H. Characterization of (111)In and (177)Lu-labeled antibodies binding to CD44v6 using a novel automated radioimmunoassay. J Mol Recognit. 2008;21:179–83.

    Article  PubMed  CAS  Google Scholar 

  117. Colnot DR, Ossenkoppele GJ, Roos JC, et al. Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Re labeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study. Clin Cancer Res. 2002;8:3401–6.

    PubMed  CAS  Google Scholar 

  118. Borjesson PK, Jauw YW, de Bree R, et al. Radiation dosimetry of 89Zr-labeled chimeric monoclonal antibody U36 as used for immuno-PET in head and neck cancer patients. J Nucl Med. 2009;50:1828–36.

    Article  PubMed  Google Scholar 

  119. Borjesson PK, Postema EJ, Roos JC, et al. Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2003;9:3961S–72S.

    PubMed  Google Scholar 

  120. Tijink BM, Buter J, de Bree R, et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res. 2006;12:6064–72.

    Article  PubMed  CAS  Google Scholar 

  121. Sauter A, Kloft C, Gronau S, et al. Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck. Int J Oncol. 2007;30:927–35.

    PubMed  CAS  Google Scholar 

  122. Rupp U, Schoendorf-Holland E, Eichbaum M, et al. Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study. Anticancer Drugs. 2007;18:477–85.

    Article  PubMed  CAS  Google Scholar 

  123. Gurtner K, Hessel F, Eicheler W, et al. Combined treatment of the immunoconjugate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo. Radiother Oncol. 2011. doi:10.1016/j.radonc.2011.10.013

  124. 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 Off J Am Soc Clin Oncol. 2007;25:3766–73.

    Article  CAS  Google Scholar 

  125. Shirai K, O'Brien PE. Molecular targets in squamous cell carcinoma of the head and neck. Curr Treat Options in Oncol. 2007;8:239–51.

    Article  Google Scholar 

  126. Williamson SK, Moon J, Huang CH, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:3330–5.

    Article  CAS  Google Scholar 

  127. Sano D, Kawakami M, Fujita K, et al. Antitumor effects of ZD6474 on head and neck squamous cell carcinoma. Oncol Rep. 2007;17:289–95.

    PubMed  CAS  Google Scholar 

  128. Gustafson DL, Frederick B, Merz AL, Raben D. 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.

    Article  PubMed  CAS  Google Scholar 

  129. Del Campo JM, Hitt R, Sebastian P, et al. Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck. Br J Cancer. 2011;105:618–27.

    Article  PubMed  CAS  Google Scholar 

  130. Johnson FM, Saigal B, Talpaz M, Donato NJ. 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 Off J Am Assoc Cancer Res. 2005;11:6924–32.

    Article  CAS  Google Scholar 

  131. Okamoto I, Kaneda H, Satoh T, et al. Phase I safety, pharmacokinetic, and biomarker study of BIBF 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther. 2010;9:2825–33.

    Article  PubMed  CAS  Google Scholar 

  132. Ledermann JA, Hackshaw A, Kaye S, et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29:3798–804.

    Article  CAS  Google Scholar 

  133. Chung CH, Aulino J, Muldowney NJ, et al. Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2010;21:864–70.

    Article  CAS  Google Scholar 

  134. Dudek AZ, Lesniewski-Kmak K, Shehadeh NJ, et al. Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer. 2009;100:1379–84.

    Article  PubMed  CAS  Google Scholar 

  135. 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.

    Article  PubMed  CAS  Google Scholar 

  136. Masuda M, Suzui M, Yasumatu R, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002;62:3351–5.

    PubMed  CAS  Google Scholar 

  137. Grandis JR, Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A. 2000;97:4227–32.

    Article  PubMed  CAS  Google Scholar 

  138. Leeman RJ, Lui VW, Grandis JR. STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther. 2006;6:231–41.

    Article  PubMed  CAS  Google Scholar 

  139. Arany I, Chen SH, Megyesi JK, et al. Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck. Cancer Lett. 2003;199:83–9.

    Article  PubMed  CAS  Google Scholar 

  140. Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96:56–67.

    Article  PubMed  CAS  Google Scholar 

  141. Noel G, Godon C, Fernet M, et al. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther. 2006;5:564–74.

    Article  PubMed  CAS  Google Scholar 

  142. Amornphimoltham P, Patel V, Sodhi A, et al. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res. 2005;65:9953–61.

    Article  PubMed  CAS  Google Scholar 

  143. Molinolo AA, Hewitt SM, Amornphimoltham P, et al. Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13:4964–73.

    Article  CAS  Google Scholar 

  144. Schmitz S, Kaminsky-Forrett MC, Henry S, et al. Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008–02). Ann Oncol. 2012. doi:10.1093/annonc/mdr574.

  145. Yin X, Zhang H, Burrows F, Zhang L, Shores CG. Potent activity of a novel dimeric heat shock protein 90 inhibitor against head and neck squamous cell carcinoma in vitro and in vivo. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:3889–96.

    Article  CAS  Google Scholar 

  146. Kao J, Genden EM, Chen CT, et al. Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer. Cancer. 2011;117:3173–81.

    Article  PubMed  CAS  Google Scholar 

  147. Wirth LJ, Haddad RI, Lindeman NI, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:6976–81.

    Article  CAS  Google Scholar 

  148. Hanrahan EO, Kies MS, Glisson BS, et al. A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2009;32:274–9.

    Article  PubMed  CAS  Google Scholar 

  149. Ferreira MB, Lima JP, and Cohen EE. Novel targeted therapies in head and neck cancer. Expert Opin Investig Drugs. 2012;21:281–95.

    Google Scholar 

  150. Preville X, Salvemini F, Giraud S, et al. Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery. Exp Cell Res. 1999;247:61–78.

    Article  PubMed  CAS  Google Scholar 

  151. Thanner F, Sutterlin MW, Kapp M, et al. Heat shock protein 27 is associated with decreased survival in node-negative breast cancer patients. Anticancer Res. 2005;25:1649–53.

    PubMed  CAS  Google Scholar 

  152. Lo WY, Tsai MH, Tsai Y, et al. Identification of over-expressed proteins in oral squamous cell carcinoma (OSCC) patients by clinical proteomic analysis. Clin Chim Acta. 2007;376:101–7.

    Article  PubMed  CAS  Google Scholar 

  153. Yin X, Zhang H, Lundgren K, et al. BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy. Int J Cancer J Int Du Cancer. 2010;126:1216–25.

    CAS  Google Scholar 

  154. Dempke W, Rie C, Grothey A, Schmoll HJ. Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol. 2001;127:411–7.

    Article  PubMed  CAS  Google Scholar 

  155. Chan G, Boyle JO, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 1999;59:991–4.

    PubMed  CAS  Google Scholar 

  156. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:1770–83.

    Article  CAS  Google Scholar 

  157. Newcomb EW. Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs. 2004;15:411–9.

    Article  PubMed  CAS  Google Scholar 

  158. Le Tourneau C, Faivre S, Laurence V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010;46:3243–50.

    Article  PubMed  CAS  Google Scholar 

  159. Aldoss IT, Tashi T, Ganti AK. Seliciclib in malignancies. Expert Opin Investig Drugs. 2009;18:1957–65.

    Article  PubMed  CAS  Google Scholar 

  160. De Herdt MJ, Baatenburg de Jong RJ. HGF and c-MET as potential orchestrators of invasive growth in head and neck squamous cell carcinoma. Front Biosci J Virtual Libr. 2008;13:2516–26.

    Article  Google Scholar 

  161. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1–26.

    Article  PubMed  CAS  Google Scholar 

  162. Knudsen BS, Vande Woude G. Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev. 2008;18:87–96.

    Article  PubMed  CAS  Google Scholar 

  163. Eder JP, Shapiro GI, Appleman LJ, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:3507–16.

    Article  CAS  Google Scholar 

  164. Rosen LS, Senzer N, Mekhail T, et al. A phase I dose-escalation study of Tivantinib (ARQ 197) in adult patients with metastatic solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:7754–64.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Unit of Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden

    S. K. Kundu & M. Nestor

  2. Unit of Otolaryngology and Head & Neck Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    M. Nestor

  3. Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, 751 85, Uppsala, Sweden

    M. Nestor

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Kundu, S.K., Nestor, M. Targeted therapy in head and neck cancer. Tumor Biol. 33, 707–721 (2012). https://doi.org/10.1007/s13277-012-0350-2

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