Molecular-Targeted Chemotherapy for Head and Neck Squamous Cell Carcinoma



The head and neck region hosts the intersection of several essential organ systems which provide the vital functions of respiration, swallowing, communication and airway protection. Therapeutic modalities designed to treat squamous cell carcinoma (SCC) of the head and neck, including surgery, chemotherapy, and radiation therapy can therefore result in devastating physical and psychological­ consequences. Recent advances in our understanding of cancer biology have revealed many potential therapeutic targets and have started to provide clinicians with a selective means to treat patients with head and neck SCC, limiting treatment morbidity while maintaining patient survival. Despite this initial promise, only a few of these molecular-targeted chemotherapies are currently in established clinical use, with the majority under ongoing preclinical and clinical trial evaluation. Future molecular-targeted chemotherapy will compliment existing therapeutic strategies before ultimately reducing the morbidity of current treatment options while maintaining or improving survival. We review the current status of the preclinical and clinical work on these putative cancer-associated molecules and the proposed strategies to exploit them for targeted tumor cell death.


Human Papilloma Virus Human Papilloma Virus Infection Human Papilloma Virus Vaccine 


  1. Abidoye OO, Cohen EE, Wong SJ et al. (2006) A phase II study of lapatinib (GW572016) in recuurent/metastatic (R/M). squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 24:5568 [abstract]Google Scholar
  2. Allen CT, Ricker JL, Chen Z, Van Waes C (2007) Role of activated nuclear factor-kappaB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck 29:959–971CrossRefPubMedGoogle Scholar
  3. Allen C, Saigal K, Nottingham L et al. (2008) Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-k B subunits in head and neck cancer. Clin Cancer Res 14:4175–4185CrossRefPubMedGoogle Scholar
  4. Alvarez-Salas LM, DiPaolo JA (2007) Molecular approaches to cervical cancer therapy. Curr Drug Discov Technol 4:208–219CrossRefPubMedGoogle Scholar
  5. Ang KK, Berkey BA, Tu X et al. (2002) Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350–7356PubMedGoogle Scholar
  6. Argiris A, Cohen E, Karrison T et al. (2006) A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther 5:766–770PubMedGoogle Scholar
  7. Ashimori N, Zeitlin BD, Zhang Z et al. (2009) TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Mol Cancer Ther 8:893–903CrossRefPubMedGoogle Scholar
  8. Avissar M, Christensen BC, Kelsey KT et al. (2009) MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res 15:2850–2855CrossRefPubMedGoogle Scholar
  9. Azmi AS, Mohammad RM (2009) Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol 218:13–21CrossRefPubMedGoogle Scholar
  10. Barnes CJ, Ohshiro K, Rayala SK et al. (2007) Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res 13:4291–4299CrossRefPubMedGoogle Scholar
  11. Bonner JA, Harari PM, Giralt J et al. (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578CrossRefPubMedGoogle Scholar
  12. Burtness B, Goldwasser MA, Flood W et al. (2005) 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 23:8646–8654CrossRefPubMedGoogle Scholar
  13. Chang SS, Jiang WW, Smith I et al. (2008) MicroRNA alterations in head and neck squamous cell carcinoma. Int J Cancer 123:2791–2797CrossRefPubMedGoogle Scholar
  14. Childs G, Fazzari M, Kung G et al. (2009) Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol 174:736–745CrossRefPubMedGoogle Scholar
  15. Chua JH, Armugam A, Jeyaseelan K (2009) MicroRNAs: biogenesis, function and applications. Curr Opin Mol Ther 11:189–199PubMedGoogle Scholar
  16. Clayman GL, el-Naggar AK, Lippman SM et al. (1998) Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 16:2221–2232PubMedGoogle Scholar
  17. Clayman GL, Frank DK, Bruso PA et al. (1999) Adenovirus-mediated wild-type p53 gene transfer as a surgical adjuvant in advanced head and neck cancers. Clin Cancer Res 5:1715–1722PubMedGoogle Scholar
  18. Cohen EE, Rosen F, Stadler WM et al. (2003) Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 21:1980–1987CrossRefPubMedGoogle Scholar
  19. Cohen EE, Kane MA, List MA et al. (2005) 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 11:8418–8424CrossRefPubMedGoogle Scholar
  20. Cohen EE, Davis DW, Karrison TG et al. (2009) Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 10:247–257CrossRefPubMedGoogle Scholar
  21. Colnot DR, Nieuwenhuis EJ, Kuik DJ et al. (2004) Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients. Clin Cancer Res 10:7827–7833CrossRefPubMedGoogle Scholar
  22. Colombo J, Fachel AA, De Freitas CM et al. (2009) Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma. Oncol Rep 21:649–663PubMedGoogle Scholar
  23. Costa FF (2009) Non-coding RNAs and new opportunities for the private sector. Drug Discov Today 14:446–452CrossRefPubMedGoogle Scholar
  24. Duan J, Friedman J, Nottingham L et al. (2007) Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 6:37–50CrossRefPubMedGoogle Scholar
  25. Egloff AM, Grandis JR (2008) Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer. Semin Oncol 35:286–297CrossRefPubMedGoogle Scholar
  26. Elser C, Siu LL, Winquist E et al. (2007) 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 25:3766–3773CrossRefPubMedGoogle Scholar
  27. Fiskus W, Buckley K, Rao R et al. (2009) Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 8:939–950PubMedGoogle Scholar
  28. Fury MG, Zahalsky A, Wong R et al. (2007) A Phase II study of SU5416 in patients with advanced or recurrent head and neck cancers. Invest New Drugs 25:165–172CrossRefPubMedGoogle Scholar
  29. Gillison ML, GLisson BS, O’Leary E et al. (2006) Phase II trial of trastuzumab (T), paclitaxel (P) and cisplatin (C) in metastatic (M) or recurrent (R) head and neck squamous cell carcinoma (HNSCC): response by tumor EGFR and HER2/neu status [abstract]. J Clin Oncol 24:18CrossRefGoogle Scholar
  30. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  31. Harrington KJ, El-Hariry IA, Holford CS et al. (2009) Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. J Clin Oncol 27:1100–1107CrossRefPubMedGoogle Scholar
  32. Hsu KF, Hung CF, Cheng WF et al. (2001) Enhancement of suicidal DNA vaccine potency by linking Mycobacterium tuberculosis heat shock protein 70 to an antigen. Gene Ther 8:376–383CrossRefPubMedGoogle Scholar
  33. Joensuu H (2008) Systemic chemotherapy for cancer: from weapon to treatment. Lancet Oncol 9:304CrossRefPubMedGoogle Scholar
  34. Kaiser J (2009) Looking for a target on every tumor. Science 326:218–220CrossRefPubMedGoogle Scholar
  35. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132CrossRefPubMedGoogle Scholar
  36. Karamouzis MV, Grandis JR, Argiris A (2007a) Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA 298:70–82CrossRefPubMedGoogle Scholar
  37. Karamouzis MV, Argiris A, Grandis JR (2007b) Clinical applications of gene therapy in head and neck cancer. Curr Gene Ther 7:446–457CrossRefPubMedGoogle Scholar
  38. Kidani K, Osaki M, Tamura T et al. (2009) High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas. Oral Oncol 45:39–46CrossRefPubMedGoogle Scholar
  39. Kondo N, Ishiguro Y, Kimura M et al. (2008) Antitumor effect of gefitinib on head and neck squamous cell carcinoma enhanced by trastuzumab. Oncol Rep 20:373–378PubMedGoogle Scholar
  40. Lai SY, Koppikar P, Thomas SM et al. (2009) Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms. J Clin Oncol 27:1235–42CrossRefPubMedGoogle Scholar
  41. Lallemant B, Evrard A, Combescure C (2009) Clinical relevance of nine transcriptional molecular markers for the diagnosis of head and neck squamous cell carcinoma in tissue and saliva rinse. BMC Cancer 9:370CrossRefPubMedGoogle Scholar
  42. Le Tourneau C, Siu LL (2008) Molecular-targeted therapies in the treatment of squamous cell carcinomas of the head and neck. Curr Opin Oncol 20:256–263CrossRefPubMedGoogle Scholar
  43. Le Tourneau C, Faivre S, Siu LL (2009) Molecular targeted therapy of head and neck cancer: review and clinical development challenges. Eur J Cancer 43:2457–2466CrossRefGoogle Scholar
  44. Lee YS, Dutta A (2006) MicroRNAs: small but potent oncogenes or tumor suppressors. Curr Opin Investig Drugs 7:560–564PubMedGoogle Scholar
  45. Li R, Zang Y, Li C et al. (2009) ABT-737 synergizes with chemotherapy to kill head and neck squamous cell carcinoma cells via a Noxa-mediated pathway. Mol Pharmacol 75:1231–1239CrossRefPubMedGoogle Scholar
  46. Lin CJ, Grandis JR, Carey TE et al. (2007) Head and neck squamous cell carcinoma cell lines: established models and rationale for selection. Head Neck 29:163–188CrossRefPubMedGoogle Scholar
  47. Macdonald GC, Rasamoelisolo M, Entwistle J et al. (2009) A phase I clinical study of intratumorally administered VB4-845, an anti-epithelial cell adhesion molecule recombinant fusion protein, in patients with squamous cell carcinoma of the head and neck. Med Oncol 26:257–264CrossRefPubMedGoogle Scholar
  48. Michaud WA, Nichols AC et al. (2009) Bcl-2 blocks cisplatin-induced apoptosis and predicts poor outcome following chemoradiation treatment in advanced oropharyngeal squamous cell carcinoma. Clin Cancer Res 15:1645–1654CrossRefPubMedGoogle Scholar
  49. Negrini M, Nicoloso MS, Calin GA (2009) MicroRNAs and cancer–new paradigms in molecular oncology. Curr Opin Cell Biol 21:470–479CrossRefPubMedGoogle Scholar
  50. Nozawa H, Tadakuma T, Ono T et al. (2006) Small interfering RNA targeting epidermal growth factor receptor enhances chemosensitivity to cisplatin, 5-fluorouracil and docetaxel in head and neck squamous cell carcinoma. Cancer Sci 97:1115–1124CrossRefPubMedGoogle Scholar
  51. Ogawa T, Furukawa T, Shiga K et al. (2009) A cDNA microarray analysis identifies 52 genes associated with cis-diamminedichloroplatinum susceptibility in head and neck squamous cell carcinoma cell lines. Eur Arch Otorhinolaryngol. doi:10.1007/s00405-009-0976-xPubMedGoogle Scholar
  52. Okamoto A, Chikamatsu K, Sakakura K et al. (2009) Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol 45:633–639CrossRefPubMedGoogle Scholar
  53. Oliver CL, Bauer JA, Wolter KG et al. (2004) In vitro effects of the BH3 mimetic, (-).-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res 10:7757–7763CrossRefPubMedGoogle Scholar
  54. Oridate N, Kim HJ, Xu X et al. (2005) Growth inhibition of head and neck squamous carcinoma cells by small interfering RNAs targeting eIF4E or cyclin D1 alone or combined with cisplatin. Cancer Biol Ther 4:318–323CrossRefPubMedGoogle Scholar
  55. Peng Z (2005) Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 16:1016–1027CrossRefPubMedGoogle Scholar
  56. Prince ME, Sivanandan R, Kaczorowski A et al. (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978CrossRefPubMedGoogle Scholar
  57. Psyrri A, Gouveris P, Vermorken JB (2009) Human papillomavirus-related head and neck tumors: clinical and research implication. Curr Opin Oncol 21:201–205CrossRefPubMedGoogle Scholar
  58. Raymond E, Alexandre J, Faivre S et al. (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347CrossRefPubMedGoogle Scholar
  59. Rocco JW, Leong CO, Kuperwasser N et al. (2006) p63 mediates survival in squamous cell ­carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9:45–56CrossRefPubMedGoogle Scholar
  60. Sattler M, Abidoye O, Salgia R (2008) EGFR-targeted therapeutics: focus on SCCHN and NSCLC. ScientifiWorldJournal 8:909–919CrossRefGoogle Scholar
  61. Seiwert TY, Haraf DJ, Cohen EE et al. (2008) Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol 26:1732–1741CrossRefPubMedGoogle Scholar
  62. Seiwert TY, Jagadeeswaran R, Faoro L et al. (2009) The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res 69:3021–3031CrossRefPubMedGoogle Scholar
  63. Silveira NJ, Varuzza L, Machado-Lima A et al. (2008) Searching for molecular markers in head and neck squamous cell carcinomas (HNSCC) by statistical and bioinformatic analysis of larynx-derived SAGE libraries. BMC Med Genomics 1:56CrossRefPubMedGoogle Scholar
  64. Siu LL, Soulieres D, Chen EX et al. (2007) 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 25:2178–2183CrossRefPubMedGoogle Scholar
  65. Soulieres D, Senzer NN, Vokes EE et al. (2004) 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 22:77–85CrossRefPubMedGoogle Scholar
  66. Stewart JS, Cohen EE, Licitra L et al. (2009) Phase III study of gefitinib 250 compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 27:1864–1871CrossRefPubMedGoogle Scholar
  67. Sunwoo JB, Chen Z, Dong G et al. (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7:1419–1428PubMedGoogle Scholar
  68. Vermorken JB, Trigo J, Hitt R et al. (2007) 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 25:2171–2177CrossRefPubMedGoogle Scholar
  69. Vermorken JB, Mesia R, Rivera F et al. (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127CrossRefPubMedGoogle Scholar
  70. Vidal L, Gillison ML (2008) Human papillomavirus in HNSCC: recognition of a distinct disease type. Hematol Oncol Clin North Am 22:1125–1142CrossRefPubMedGoogle Scholar
  71. Visone R, Croce CM (2009) MiRNAs and cancer. Am J Pathol 174:1131–1138CrossRefPubMedGoogle Scholar
  72. Wang Y, Tao ZZ, Chen SM et al. (2008) Application of combination of short hairpin RNA segments for silencing VEGF, TERT and Bcl-xl expression in laryngeal squamous carcinoma. Cancer Biol Ther 7:896–901CrossRefPubMedGoogle Scholar
  73. Wolter KG, Wang SJ, Henson BS et al. (2006) (-)-gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo. Neoplasia 8:163–172CrossRefPubMedGoogle Scholar
  74. Yanamoto S, Kawasaki G, Yoshitomi I et al. (2007) Clinicopathologic significance of EpCAM expression in squamous cell carcinoma of the tongue and its possibility as a potential target for tongue cancer gene therapy. Oral Oncol 43:869–877CrossRefPubMedGoogle Scholar
  75. Yang CH, Kies MS, Glisson B et al. (2005) A phase II study of lonafarnib (SCH66336) in patients with chemo-refractory advanced head and neck squamous cell carcinoma (HNSCC. [abstract]. J Clin Oncol 23:16Google Scholar
  76. Zhang SW, Xiao SW, Liu CQ et al. (2003) Treatment of head and neck squamous cell carcinoma by recombinant adenovirus-p53 combined with radiotherapy: a phase II clinical trial of 42 cases. Zhonghua Yi Xue Za Zhi 83:2023–2028PubMedGoogle Scholar
  77. Zhang SW, Xiao SW, Liu CQ et al. (2005) Recombinant adenovirus-p53 gene therapy combined with radiotherapy for head and neck squamous-cell carcinoma. Zhonghua Zhong Liu Za Zhi 27:426–428PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of SurgeryMassachusetts General HospitalBostonUSA

Personalised recommendations