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Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives

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Abstract

Despite improvements in functional outcomes attributable to advances in radiotherapy, chemotherapy, surgical techniques, and imaging techniques, survival in head and neck squamous cell carcinoma (HNSCC) patients has improved only marginally during the last couple of decades, and optimal therapy has yet to be devised. Genomic complexity and intratumoral genetic heterogeneity may contribute to treatment resistance and the propensity for locoregional recurrence. Countering this, it demands a significant effort from both basic and clinical scientists in the search for more effective targeted therapies. Recent genomewide studies have provided valuable insights into the genetic basis of HNSCC, uncovering potential new therapeutic opportunities. In addition, several studies have elucidated how inflammatory, immune, and stromal cells contribute to the particular properties of these neoplasms. In the present review, we introduce recent findings on genomic aberrations resulting from whole-genome sequencing of HNSCC, we discuss how the particular microenvironment affects the pathogenesis of this disease, and we describe clinical trials exploring new perspectives on the use of combined genetic and cellular targeted therapies.

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References

  1. Leemans, C. R., Braakhuis, B. J., & Brakenhoff, R. H. (2011). The molecular biology of head and neck cancer. Nature Reviews Cancer, 11, 9–22.

    Article  CAS  PubMed  Google Scholar 

  2. Blot, W. J., McLaughlin, J. K., Winn, D. M., Austin, D. F., Greenberg, R. S., & Preston-Martin, S. et al. (1988). Smoking and drinking in relation to oral and pharyngeal cancer. 48:3282–7.

  3. Znaor, A., Brennan, P., Gajalakshmi, V., Mathew, A., Shanta, V., & Varghese, C. et al (2003). Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. 105:681–6.

  4. Talamini, R., Vaccarella, S., Barbone, F., Tavani, A., Vecchia, C. L., & Herrero, R. et al (2000). Oral hygiene, dentition, sexual habits and risk of oral cancer. 83:1238–42.

  5. Gillison, M. L., Koch, W. M., Capone, R. B., Spafford, M., Westra, W. H., & Wu, L. et al (2000). Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. 92:709–20.

  6. Begum, S., Cao, D., Gillison, M., Zahurak, M., Westra, & W. H. (2005). Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. 11:5694–9.

  7. Andl, T., Kahn, T., Pfuhl, A., Nicola, T., Erber, R.,& Conradt, C. et al. (1998). Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. 58:5–13.

  8. Paz, I. B., Cook, N., Odom-Maryon, T., Xie, Y., & Wilczynski, S. P. (1997). Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer’s tonsillar ring. 79:595–604.

  9. Stein, A. P., Saha, S., Kraninger, J. L., Swick, A. D., Yu, M., Lambert, P. F., et al. (2015). Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review. Cancer Journal of Sudbury Mass, 21, 138–46. doi:10.1097/PPO.0000000000000115.

    Article  Google Scholar 

  10. Boscolo-Rizzo, P., Mistro, A. D., Bussu, F., Lupato, V., Baboci, L., Almadori, G., et al. (2013). New insights into human papillomavirus-associated head and neck squamous cell carcinoma. Acta Otorhinolaryngologica Italica, 33, 77–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Boscolo-Rizzo, P., Gava, A., Marchiori, C., Baggio, V., & Mosto, M. C. D. (2011). Functional organ preservation in patients with locoregionally advanced head and neck squamous cell carcinoma treated by platinum-based multidrug induction chemotherapy and concurrent chemoradiotherapy. Annals of Oncology, 22, 1894–901.

    Article  CAS  PubMed  Google Scholar 

  12. Ghi, M. G., Paccagnella, A., Ferrari, D., Foa, P., Cossu Rocca, M., & Elena, V. (2014). Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction docetaxel/cisplatin/5-fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study (NCT01086826). Journal of Clinical Oncology 5s.

  13. Vermorken, J. B., Remenar, E., van Herpen, C., Gorlia, T., Mesia, R., Degardin, M., et al. (2007). Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. New England Journal of Medicine, 357, 1695–704.

    Article  CAS  PubMed  Google Scholar 

  14. Bonner, J. A., Harari, P. M., Giralt, J., Cohen, R. B., Jones, C. U., Sur, R. K., et al. (2010). 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. The Lancet Oncology, 11, 21–8.

    Article  CAS  PubMed  Google Scholar 

  15. Pulte, D., & Brenner, H. (2010). Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. The Oncologist, 15, 994–1001. doi:10.1634/theoncologist.2009-0289.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Network, C. G. A. (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517, 576–82.

    Article  CAS  Google Scholar 

  17. Mroz, E. A., Tward, A. M., Hammon, R. J., Ren, Y., & Rocco, J. W. (2015). Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the cancer genome Atlas. PLoS Medicine, 12, e1001786.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Boscolo-Rizzo, P., Rampazzo, E., Perissinotto, E., Piano, M. A., Giunco, S., & Baboci, L. et al. (2015). Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma. Oral Oncology.

  19. Lartigau, E. F., Tresch, E., Thariat, J., Graff, P., Coche-Dequeant, B., Benezery, K., et al. (2013). Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer. Radiothermal Oncology Journal of European Society of Thermal Radiololgy Oncology, 109, 281–5. doi:10.1016/j.radonc.2013.08.012.

    Article  CAS  Google Scholar 

  20. Putten, L., Bree, R., Doornaert, P. A., Buter, J., Eerenstein, S. E. J., Rietveld, D. H. F., et al. (2015). Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review. Acta Otorhinolaryngol Ital Organo Uff Della Soc Ital Otorinolaringol E Chir Cerv-Facc, 35, 162–72.

    CAS  Google Scholar 

  21. Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S., et al. (2008). Platinum-based chemotherapy plus cetuximab in head and neck cancer. New England Journal of Medicine, 359, 1116–27.

    Article  CAS  PubMed  Google Scholar 

  22. Machiels, J.-P., Subramanian, S., Ruzsa, A., Repassy, G., Lifirenko, I., Flygare, A., et al. (2011). Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncology, 12, 333–43. doi:10.1016/S1470-2045(11)70034-1.

    Article  CAS  PubMed  Google Scholar 

  23. Machiels, J.-P. H., Haddad, R. I., Fayette, J., Licitra, L. F., Tahara, M., Vermorken, J. B., et al. (2015). Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncology, 16, 583–94. doi:10.1016/S1470-2045(15)70124-5.

    Article  CAS  PubMed  Google Scholar 

  24. O’Rorke, M. A., Ellison, M. V., Murray, L. J., Moran, M., James, J., & Anderson, L. A. (2012). Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncology, 48, 1191–201.

    Article  PubMed  Google Scholar 

  25. Vainshtein, J. M., Spector, M. E., Ibrahim, M., Bradford, C. R., Wolf, G. T., Stenmark, M. H., et al. (2015). Matted nodes: high distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer. Head and Neck. doi:10.1002/hed.24105.

    Google Scholar 

  26. Vermorken, J. B., Stöhlmacher-Williams, J., Davidenko, I., Licitra, L., Winquist, E., Villanueva, C., et al. (2013). Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncology, 14, 697–710. doi:10.1016/S1470-2045(13)70181-5.

    Article  CAS  PubMed  Google Scholar 

  27. Vermorken, J. B., Psyrri, A., Mesía, R., Peyrade, F., Beier, F., de Blas, B., et al. (2014). Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Annals of Oncology Official Journal of European Society of Medical Oncology ESMO, 25, 801–7. doi:10.1093/annonc/mdt574.

    Article  CAS  Google Scholar 

  28. Ang, K. K., Zhang, Q., Rosenthal, D. I., Nguyen-Tan, P. F., Sherman, E. J., Weber, R. S., et al. (2014). Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 32, 2940–50.

    Article  CAS  Google Scholar 

  29. Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., et al. (2011). Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science, 333, 1154–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., et al. (2011). The mutational landscape of head and neck squamous cell carcinoma. Science, 333, 1157–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Akagi, K., Li, J., Broutian, T. R., Padilla-Nash, H., Xiao, W., Jiang, B., et al. (2014). Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Research, 24, 185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Parfenov, M., Pedamallu, C. S., Gehlenborg, N., Freeman, S. S., Danilova, L., Bristow, C. A., et al. (2014). Characterization of HPV and host genome interactions in primary head and neck cancers. Proceedings of National Academy of Sciences USA, 111, 15544–9.

    Article  CAS  Google Scholar 

  33. Seiwert, T. Y., Zuo, Z., Keck, M. K., Khattri, A., Pedamallu, C. S., & Stricker, T. P. et al. (2014). Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clinical Cancer Research

  34. Lyford-Pike, S., Peng, S., Young, G. D., Taube, J. M., Westra, W. H., Akpeng, B., et al. (2013). Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Research, 73, 1733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kesselring, R., Thiel, A., Pries, R., Fichtner-Feigl, S., Brunner, S., & Seidel, P. (2014). The complement receptors CD46, CD55 and CD59 are regulated by the tumour microenvironment of head and neck cancer to facilitate escape of complement attack. European Journal of Cancer Oxford England 1990, 50, 2152–61. doi:10.1016/j.ejca.2014.05.005.

    CAS  Google Scholar 

  36. Lechner, M., Frampton, G. M., Fenton, T., Feber, A., Palmer, G., Jay, A., et al. (2013). Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV− tumors. Genome Medicine, 5, 49.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chung, C. H., Parker, J. S., Karaca, G., Wu, J., Funkhouser, W. K., Moore, D., et al. (2004). Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell, 5, 489–500.

    Article  CAS  PubMed  Google Scholar 

  38. Walter, V., Yin, X., Wilkerson, M. D., Cabanski, C. R., Zhao, N., Du, Y., et al. (2013). Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PloS One, 8, e56823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pickering, C. R., Zhang, J., Yoo, S. Y., Bengtsson, L., Moorthy, S., Neskey, D. M., et al. (2013). Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discovery, 3, 770–81.

    Article  CAS  PubMed  Google Scholar 

  40. Tabor, M. P., Brakenhoff, R. H., Ruijter-Schippers, H. J., Van Der Wal, J. E., Snow, G. B., Leemans, C. R., et al. (2002). Multiple head and neck tumors frequently originate from a single preneoplastic lesion. American Journal of Pathology, 161, 1051–60. doi:10.1016/S0002-9440(10)64266-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brosh, R., & Rotter, V. (2009). When mutants gain new powers: news from the mutant p53 field. Nature Reviews Cancer, 9, 701–13. doi:10.1038/nrc2693.

    CAS  PubMed  Google Scholar 

  42. Muller, P. A. J., & Vousden, K. H. (2013). p53 mutations in cancer. Nature Cell Biology, 15, 2–8. doi:10.1038/ncb2641.

    Article  CAS  PubMed  Google Scholar 

  43. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63, 1129–36.

    Article  CAS  PubMed  Google Scholar 

  44. Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature, 387, 296–9. doi:10.1038/387296a0.

    Article  CAS  PubMed  Google Scholar 

  45. Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., et al. (2009). A mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell, 137, 87–98.

    Article  CAS  PubMed  Google Scholar 

  46. Peltonen, J. K., Helppi, H. M., Paakko, P., Turpeenniemi-Hujanen, T., & Vahakangas, K. H. (2010). p53 in head and neck cancer: functional consequences and environmental implications of TP53 mutations. Head Neck Oncology 2:36–3284 – 2–36.

  47. Poeta, M. L., Manola, J., Goldwasser, M. A., Forastiere, A., Benoit, N., Califano, J. A., et al. (2007). TP53 mutations and survival in squamous-cell carcinoma of the head and neck. New England Journal of Medicine, 357, 2552–61. doi:10.1056/NEJMoa073770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Perrone, F., Bossi, P., Cortelazzi, B., Locati, L., Quattrone, P., Pierotti, M. A., et al. (2010). TP53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28, 761–6.

    Article  CAS  Google Scholar 

  49. Skinner, H. D., Sandulache, V. C., Ow, T. J., Meyn, R. E., Yordy, J. S., Beadle, B. M., et al. (2012). TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clinical Cancer Research Official Journal of American Association Cancer Research, 18, 290–300.

    Article  CAS  Google Scholar 

  50. Lukas, J., Parry, D., Aagaard, L., Mann, D. J., Bartkova, J., Strauss, M., et al. (1995). Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature, 375, 503–6. doi:10.1038/375503a0.

    Article  CAS  PubMed  Google Scholar 

  51. Weinberg, R. A. (1995). The retinoblastoma protein and cell cycle control. Cell, 81, 323–30.

    Article  CAS  PubMed  Google Scholar 

  52. Gallagher, S., Kefford, R. F., & Rizos, H. (2005). Enforced expression of p14ARF induces p53-dependent cell cycle arrest but not apoptosis. Cell Cycle Georget Texas, 4, 465–72.

    Article  CAS  Google Scholar 

  53. Sherr, C. J., & McCormick, F. (2002). The RB and p53 pathways in cancer. Cancer Cell, 2, 103–12.

    Article  CAS  PubMed  Google Scholar 

  54. Sharpless, N. E. (2005). INK4a/ARF: a multifunctional tumor suppressor locus. Mutation Research, 576, 22–38. doi:10.1016/j.mrfmmm.2004.08.021.

    Article  CAS  PubMed  Google Scholar 

  55. Miyamoto, R., Uzawa, N., Nagaoka, S., Hirata, Y., & Amagasa, T. (2003). Prognostic significance of cyclin D1 amplification and overexpression in oral squamous cell carcinomas. Oral Oncology, 39, 610–8.

    Article  CAS  PubMed  Google Scholar 

  56. Wiest, T., Schwarz, E., Enders, C., Flechtenmacher, C., & Bosch, F. X. (2002). Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. 21:1510–7.

  57. Classon, M., & Harlow, E. (2002). The retinoblastoma tumour suppressor in development and cancer 2:910–7. doi: 10.1038/nrc950.

  58. Nemunaitis, J., Clayman, G., Agarwala, S. S., Hrushesky, W., Wells, J. R., & Moore, C. et al. (2009). Biomarkers predict p53 gene therapy efficacy in recurrent squamous cell carcinoma of the head and neck. 15:7719–25. doi: 10.1158/1078-0432.CCR-09-1044.

  59. Finn, R. S., Crown, J. P., Lang, I., Boer, K., Bondarenko, I. M., Kulyk, S. O., et al. (2015). The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncology, 16, 25–35. doi:10.1016/S1470-2045(14)71159-3.

    Article  CAS  PubMed  Google Scholar 

  60. Loren. A phase I trial of the addition of the CDK 4/6 inhibitor palbociclib to cetuximab in patients with incurable head and neck squamous cell carcinoma (HNSCC). Journal of Clinical Oncology n.d.

  61. Kumar, S., Biswas, M., & Jose, T. (2015). HPV vaccine: current status and future directions. 71:171–7. doi: 10.1016/j.mjafi.2015.02.006.

  62. Monie, A., Tsen, S. W., Hung, C. F., & Wu, T. C. (2009). Therapeutic HPV DNA vaccines. 8:1221–35.

  63. Voskens, C. J., Sewell, D., Hertzano, R., DeSanto, J., Rollins, S., & Lee, M. et al. (2012). Induction of MAGE-A3 and HPV-16 immunity by Trojan vaccines in patients with head and neck carcinoma. 34:1734–46.

  64. Hung, C.-F., Ma, B., Monie, A., Tsen, S.-W., & Wu, T.-C. (2008). Therapeutic human papillomavirus vaccines: current clinical trials and future directions. Expert Opinion on Biological Therapy, 8, 421–39. doi:10.1517/14712598.8.4.421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cory, L., & Chu, C. (2014). ADXS-HPV: a therapeutic Listeria vaccination targeting cervical cancers expressing the HPV E7 antigen. Human Vaccines Immunothermology, 10, 3190–5. doi:10.4161/hv.34378.

    Article  Google Scholar 

  66. Liu, P., Cheng, H., Roberts, T. M., & Zhao, J. J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. 8:627–44.

  67. Castellano, E., & Downward, J. (2011). RAS interaction with PI3K: more than just another effector pathway. 2:261–74.

  68. Jimeno, A., Shirai, K., Choi, M., Laskin, J., Kochenderfer, M., Spira, A., et al. (2015). A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Annals of Oncology, 26, 556–61. doi:10.1093/annonc/mdu574.

    Article  CAS  PubMed  Google Scholar 

  69. Jimeno, A., Bauman, J. E., Weissman, C., Adkins, D., Schnadig, I., Beauregard, P., et al. (2015). A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncology, 51, 383–8. doi:10.1016/j.oraloncology.2014.12.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: results from the first-in-human study. Journal of Clinical Oncology n.d.

  71. Nguyen, S. A., Walker, D., Gillespie, M. B., Gutkind, J. S., & Day, T. A. (2012). mTOR inhibitors and its role in the treatment of head and neck squamous cell carcinoma. Current Treatment Options in Oncology, 13, 71–81. doi:10.1007/s11864-011-0180-2.

    Article  PubMed  Google Scholar 

  72. Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Journal of Clinical Oncology n.d.

  73. Phase II study of temsirolimus and erlotinib in patients (pts) with recurrent/metastatic (R/M), platinum-refractory head and neck squamous cell carcinoma (HNSCC). Journal of Clinical Oncology n.d.

  74. Grünwald, V., Keilholz, U., Boehm, A., Guntinas-Lichius, O., Hennemann, B., Schmoll, H. J., et al. (2015). TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO). Annals of Oncology, 26, 561–7. doi:10.1093/annonc/mdu571.

    Article  PubMed  Google Scholar 

  75. Williamson, S. K., Moon, J., Huang, C. H., Guaglianone, P. P., LeBlanc, M., Wolf, G. T., et al. (2010). Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28, 3330–5. doi:10.1200/JCO.2009.25.6834.

    Article  CAS  Google Scholar 

  76. Laban, S., Steinmeister, L., Gleißner, L., Grob, T. J., Grénman, R., Petersen, C., et al. (2013). Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. Radiotherapy and Oncology, 109, 286–92. doi:10.1016/j.radonc.2013.07.003.

    Article  CAS  PubMed  Google Scholar 

  77. Lin, S. Y., Makino, K., Xia, W., Matin, A., Wen, Y., Kwong, K. Y., et al. (2001). Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nature Cell Biology, 3, 802–8. doi:10.1038/ncb0901-802.

    Article  CAS  PubMed  Google Scholar 

  78. Reddy, B. K. M., Lokesh, V., Vidyasagar, M. S., Shenoy, K., Babu, K. G., Shenoy, A., et al. (2014). Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients. Oral Oncology, 50, 498–505. doi:10.1016/j.oraloncology.2013.11.008.

    Article  CAS  PubMed  Google Scholar 

  79. Licitra, L., Mesia, R., Rivera, F., Remenar, E., Hitt, R., & Erfan, J. (2011). Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck. EXTREME Study, 22, 1078–87.

    CAS  Google Scholar 

  80. Vermorken, J. B., Trigo, J., Hitt, R., Koralewski, P., Diaz-Rubio, E., Rolland, F., 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. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 25, 2171–7. doi:10.1200/JCO.2006.06.7447.

    Article  CAS  Google Scholar 

  81. Hitt, R., Irigoyen, A., Cortes-Funes, H., Grau, J. J., García-Sáenz, J. A., Cruz-Hernandez, J. J., et al. (2012). Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Annals of Oncology. Official Journal of European Society of Medical Oncology ESMO, 23, 1016–22. doi:10.1093/annonc/mdr367.

    Article  CAS  Google Scholar 

  82. Cohen, E. E., Rosen, F., Stadler, W. M., Recant, W., Stenson, K., Huo, D., et al. (2003). Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 21, 1980–7.

    Article  CAS  Google Scholar 

  83. Kirby, A. M., A’Hern, R. P., D’Ambrosio, C., Tanay, M., Syrigos, K. N., Rogers, S. J., et al. (2006). Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer. British Journal of Cancer, 94, 631–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sok, J. C., Coppelli, F. M., Thomas, S. M., Lango, M. N., Xi, S., Hunt, J. L., et al. (2006). Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clinical Cancer Research. Official Journal of American Association of Cancer Research, 12, 5064–73.

    Article  CAS  Google Scholar 

  85. Hama, T., Yuza, Y., Suda, T., Saito, Y., Norizoe, C., Kato, T., et al. (2012). Functional mutation analysis of EGFR family genes and corresponding lymph node metastases in head and neck squamous cell carcinoma. Clinical & Experimental Metastasis, 29, 19–25.

    Article  CAS  Google Scholar 

  86. Harrington, K., Berrier, A., Robinson, M., Remenar, E., Housset, M., & de Mendoza, F. H. (2013). Randomised phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. European Journal of Cancer Oxford England 1990, 49, 1609–18.

    CAS  Google Scholar 

  87. Harrington, K., Temam, S., Mehanna, H., D’Cruz, A., Jain, M., & D’Onofrio I. et al. (2015). Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study. Journal of Clinical Oncology. JCO.2015.61.4370. doi:10.1200/JCO.2015.61.4370.

  88. Seiwert, T. Y., Fayette, J., Cupissol, D., Campo, J. M. D., Clement, P. M., Hitt, R., et al. (2014). A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Annals of Oncology. Official Journal of European Society of Medical Oncology ESMO, 25, 1813–20.

    Article  CAS  Google Scholar 

  89. Bray, S. J. (2006). Notch signalling: a simple pathway becomes complex. National Review Cell Biology, 7, 678–89.

    Article  CAS  Google Scholar 

  90. Dotto, G. P. (2009). Crosstalk of Notch with p53 and p63 in cancer growth control. National Review, 9, 587–95.

    Article  CAS  Google Scholar 

  91. Zhong, R., Bao, R., Faber, P. W., Bindokas, V. P., Bechill, J., Lingen, M. W., et al. (2015). Notch1 activation or loss promotes HPV-induced oral tumorigenesis. Cancer Research. doi:10.1158/0008-5472.CAN-15-0199.

    Google Scholar 

  92. Okuyama, R., Ogawa, E., Nagoshi, H., Yabuki, M., Kurihara, A., Terui, T., et al. (2007). p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity. Oncogene, 26, 4478–88. doi:10.1038/sj.onc.1210235.

    Article  CAS  PubMed  Google Scholar 

  93. Sun, W., Gaykalova, D. A., Ochs, M. F., Mambo, E., Arnaoutakis, D., Liu, Y., et al. (2014). Activation of the NOTCH pathway in head and neck cancer. Cancer Research, 74, 1091–104.

    Article  CAS  PubMed  Google Scholar 

  94. Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordóñez, G. R., Villamor, N., et al. (2011). Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475, 101–5. doi:10.1038/nature10113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hayes, J., Peruzzi, P. P., & Lawler, S. (2014). MicroRNAs in cancer: biomarkers, functions and therapy. Trends in Molecular Medicine, 20, 460–9. doi:10.1016/j.molmed.2014.06.005.

    Article  CAS  PubMed  Google Scholar 

  96. Büssing, I., Slack, F. J., & Grosshans, H. (2008). let-7 microRNAs in development, stem cells and cancer. Trends in Molecular Medicine, 14, 400–9. doi:10.1016/j.molmed.2008.07.001.

    Article  PubMed  CAS  Google Scholar 

  97. Suh, Y., Amelio, I., Guerrero Urbano, T., & Tavassoli, M. (2014). Clinical update on cancer: molecular oncology of head and neck cancer. Cell Death Diseases, 5, e1018. doi:10.1038/cddis.2013.548.

    Article  CAS  Google Scholar 

  98. Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., et al. (2005). RAS is regulated by the let-7 microRNA family. Cell, 120, 635–47. doi:10.1016/j.cell.2005.01.014.

    Article  CAS  PubMed  Google Scholar 

  99. Dai, Y., Xie, C.-H., Neis, J. P., Fan, C.-Y., Vural, E., & Spring, P. M. (2011). MicroRNA expression profiles of head and neck squamous cell carcinoma with docetaxel-induced multidrug resistance. Head and Neck, 33, 786–91. doi:10.1002/hed.21540.

    Article  PubMed  Google Scholar 

  100. Kimura, S., Naganuma, S., Susuki, D., Hirono, Y., Yamaguchi, A., Fujieda, S., et al. (2010). Expression of microRNAs in squamous cell carcinoma of human head and neck and the esophagus: miR-205 and miR-21 are specific markers for HNSCC and ESCC. Oncology Reports, 23, 1625–33.

    CAS  PubMed  Google Scholar 

  101. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–74. doi:10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  102. Perry, M. E. (1994). The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. Journal of Anatomy, 185(Pt 1), 111–27.

    PubMed  PubMed Central  Google Scholar 

  103. Westra, W. H. (2012). The morphologic profile of HPV-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head and Neck Pathology, 6(Suppl 1), S48–54.

    Article  PubMed  Google Scholar 

  104. Prince, M. E., Sivanandan, R., Kaczorowski, A., Wolf, G. T., Kaplan, M. J., Dalerba, P., et al. (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 104, 973–8. doi:10.1073/pnas.0610117104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Brunner, T. B., Kunz-Schughart, L. A., Grosse-Gehling, P., & Baumann, M. (2012). Cancer stem cells as a predictive factor in radiotherapy. Seminars in Radiation Oncology, 22, 151–74. doi:10.1016/j.semradonc.2011.12.003.

    Article  PubMed  Google Scholar 

  106. Fiaschi, T., & Chiarugi, P. (2012). Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. International Journal of Cell Biology, 2012, 762825. doi:10.1155/2012/762825.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Chang, C.-W., Chen, Y.-S., Chou, S.-H., Han, C.-L., Chen, Y.-J., Yang, C.-C., et al. (2014). Distinct subpopulations of head and neck cancer cells with different levels of intracellular reactive oxygen species exhibit diverse stemness, proliferation, and chemosensitivity. Cancer Research, 74, 6291–305. doi:10.1158/0008-5472.CAN-14-0626.

    Article  CAS  PubMed  Google Scholar 

  108. De Palma, M., & Lewis, C. E. (2013). Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell, 23, 277–86. doi:10.1016/j.ccr.2013.02.013.

    Article  PubMed  CAS  Google Scholar 

  109. Siveen, K. S., & Kuttan, G. (2009). Role of macrophages in tumour progression. Immunology Letters, 123, 97–102. doi:10.1016/j.imlet.2009.02.011.

    Article  CAS  PubMed  Google Scholar 

  110. Chang, K.-P., Kao, H.-K., Yen, T.-C., Chang, Y.-L., Liang, Y., Liu, S.-C., et al. (2011). Overexpression of macrophage inflammatory protein-3α in oral cavity squamous cell carcinoma is associated with nodal metastasis. Oral Oncology, 47, 108–13. doi:10.1016/j.oraloncology.2010.11.012.

    Article  CAS  PubMed  Google Scholar 

  111. Balermpas, P., Rodel, F., Liberz, R., Oppermann, J., Wagenblast, J., Ghanaati, S., et al. (2014). Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b + myeloid cells in recurrences. British Journal of Cancer, 111, 1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gabrilovich, D. I., Ostrand-Rosenberg, S., & Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nature Reviews Immunology, 12, 253–68. doi:10.1038/nri3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. 12:252–64. doi:10.1038/nrc3239.

  114. Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W-J., Topalian, S. L., & Hwu P. et al. (2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. 366:2455–65. doi:10.1056/NEJMoa1200694.

  115. Li, S., Labrecque, S., Gauzzi, M. C., Cuddihy, A. R., Wong, A. H., Pellegrini, S., et al. (1999). The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. Oncogene, 18, 5727–37.

    Article  CAS  PubMed  Google Scholar 

  116. Gastman, B. R., Atarshi, Y., Reichert, T. E., Saito, T., Balkir, L., Rabinowich, H., et al. (1999). Fas ligand is expressed on human squamous cell carcinomas of the head and neck, and it promotes apoptosis of T lymphocytes. Cancer Research, 59, 5356–64.

    CAS  PubMed  Google Scholar 

  117. Hodi, F. S., O’Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363, 711–23. doi:10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jie, H.-B., Schuler, P. J., Lee, S. C., Srivastava, R. M., Argiris, A., Ferrone, S., et al. (2015). CTLA-4+ regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Research, 75, 2200–10. doi:10.1158/0008-5472.CAN-14-2788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ham, Y., Oh, H. Y., Seo, S.-S., & Kim, M. K. (2015). Association between health behaviors and a family history of cancer among Korean women. Cancer Research Treatment. Official Journal of Korean Cancer Association. doi:10.4143/crt.2015.083.

    PubMed  PubMed Central  Google Scholar 

  120. Badoual, C., Hans, S., Merillon, N., Ryswick, C. V., Ravel, P., Benhamouda, N., et al. (2013). PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Research, 73, 128–38. doi:10.1158/0008-5472.CAN-12-2606.

    Article  CAS  PubMed  Google Scholar 

  121. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV-associated head and neck (H/N) cancer. Journal of Clinical Oncology n.d.

  122. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): preliminary results from KEYNOTE-012 expansion cohort. Journal of Clinical Oncology n.d.

  123. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. Journal of Clinical Oncology n.d.

  124. Yoshitake, Y., Fukuma, D., Yuno, A., Hirayama, M., Nakayama, H., Tanaka, T., et al. (2015). Phase II clinical trial of multiple peptide vaccination for advanced head and neck cancer patients revealed induction of immune responses and improved OS. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 21, 312–21. doi:10.1158/1078-0432.CCR-14-0202.

    Article  CAS  Google Scholar 

  125. Tang, X., Zhou, Y., Li, W., Tang, Q., Chen, R., Zhu, J., et al. (2014). T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo. Journal of Biomedical Research, 28, 468–75. doi:10.7555/JBR.28.20140066.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Lim, J. Y. H., Gerber, S. A., Murphy, S. P., & Lord, E. M. (2014). Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunology Immunothermology CII, 63, 259–71. doi:10.1007/s00262-013-1506-7.

    Article  CAS  PubMed  Google Scholar 

  127. Ikushima, H., & Miyazono, K. (2010). TGFbeta signalling: a complex web in cancer progression. Nature Reviews Cancer, 10, 415–24. doi:10.1038/nrc2853.

    Article  CAS  PubMed  Google Scholar 

  128. Schuler, P. J., Harasymczuk, M., Visus, C., Deleo, A., Trivedi, S., Lei, Y., et al. (2014). Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 20, 2433–44. doi:10.1158/1078-0432.CCR-13-2617.

    Article  CAS  Google Scholar 

  129. Swanson, M. S., & Sinha, U. K. (2015). Rationale for combined blockade of PD-1 and CTLA-4 in advanced head and neck squamous cell cancer—review of current data. Oral Oncology, 51, 12–5. doi:10.1016/j.oraloncology.2014.10.010.

    Article  CAS  PubMed  Google Scholar 

  130. Park, J., Kim, J.-M., Park, J. K., Huang, S., Kwak, S. Y., Ryu, K. A., et al. (2015). Association of p21-activated kinase-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head and Neck, 37, 953–63. doi:10.1002/hed.23695.

    Article  PubMed  Google Scholar 

  131. Geldres, C., Savoldo, B., Hoyos, V., Caruana, I., Zhang, M., Yvon, E., et al. (2014). T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 20, 962–71. doi:10.1158/1078-0432.CCR-13-2218.

    Article  CAS  Google Scholar 

  132. Kumai, T., Oikawa, K., Aoki, N., Kimura, S., Harabuchi, Y., Celis, E., et al. (2014). Tumor-derived TGF-β and prostaglandin E2 attenuate anti-tumor immune responses in head and neck squamous cell carcinoma treated with EGFR inhibitor. Journal of Translational Medicine, 12, 265. doi:10.1186/s12967-014-0265-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Fury, M. G., Baxi, S., Shen, R., Kelly, K. W., Lipson, B. L., Carlson, D., et al. (2011). Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Anticancer Research, 31, 249–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Sen, B., & Johnson, F. M. (2011). Regulation of SRC family kinases in human cancers. Journal of Signal Transduction, 2011, 865819. doi:10.1155/2011/865819.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Koppikar, P., Choi, S.-H., Egloff, A. M., Cai, Q., Suzuki, S., Freilino, M., et al. (2008). Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 14, 4284–91. doi:10.1158/1078-0432.CCR-07-5226.

    Article  CAS  Google Scholar 

  136. Shah, J.P. (1990). Cervical lymph node metastases—diagnostic, therapeutic, and prognostic implications. Oncology Williston Park N 4:61–9; discussion 72, 76.

  137. Nozawa, H., Howell, G., Suzuki, S., Zhang, Q., Qi, Y., Klein-Seetharaman, J., et al. (2008). Combined inhibition of PLC{gamma}-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 14, 4336–44. doi:10.1158/1078-0432.CCR-07-4857.

    Article  CAS  Google Scholar 

  138. Chang, C.-L., Hsu, Y.-T., Wu, C.-C., Lai, Y.-Z., Wang, C., Yang, Y.-C., et al. (2013). Dose-dense chemotherapy improves mechanisms of antitumor immune response. Cancer Research, 73, 119–27. doi:10.1158/0008-5472.CAN-12-2225.

    Article  CAS  PubMed  Google Scholar 

  139. Srivastava, R. M., Lee, S. C., Andrade Filho, P. A., Lord, C. A., Jie, H.-B., Davidson, H. C., et al. (2013). Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 19, 1858–72. doi:10.1158/1078-0432.CCR-12-2426.

    Article  CAS  Google Scholar 

  140. de Biasi, A. R., Villena-Vargas, J., & Adusumilli, P. S. (2014). Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 20, 5384–91. doi:10.1158/1078-0432.CCR-14-1298.

    Article  CAS  Google Scholar 

  141. Alfaro, C., Suarez, N., Gonzalez, A., Solano, S., Erro, L., Dubrot, J., et al. (2009). Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. British Journal of Cancer, 100, 1111–9. doi:10.1038/sj.bjc.6604965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ozao-Choy, J., Ma, G., Kao, J., Wang, G. X., Meseck, M., Sung, M., et al. (2009). The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Research, 69, 2514–22. doi:10.1158/0008-5472.CAN-08-4709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Tsuchikawa, T., Md, M. M., Yamamura, Y., Shichinohe, T., Hirano, S., & Kondo, S. (2012). The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma. Annals of Surgical Oncology, 19, 1713–9. doi:10.1245/s10434-011-1906-x.

    Article  PubMed  Google Scholar 

  144. Vanneman, M., & Dranoff, G. (2012). Combining immunotherapy and targeted therapies in cancer treatment. Nature Reviews Cancer, 12, 237–51. doi:10.1038/nrc3237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Rosenthal, E. L., & Matrisian, L. M. (2006). Matrix metalloproteases in head and neck cancer. Head and Neck, 28, 639–48. doi:10.1002/hed.20365.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Folkman, J. (2002). Role of angiogenesis in tumor growth and metastasis. Seminars in Oncology, 29, 15–8. doi:10.1053/sonc.2002.37263.

    Article  CAS  PubMed  Google Scholar 

  147. Albini, A., Tosetti, F., Benelli, R., & Noonan, D. M. (2005). Tumor inflammatory angiogenesis and its chemoprevention. Cancer Research, 65, 10637–41. doi:10.1158/0008-5472.CAN-05-3473.

    Article  CAS  PubMed  Google Scholar 

  148. Kyzas, P. A., Cunha, I. W., & Ioannidis, J. P. (2005). Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clinical Cancer Research. Official Journal of American Association Cancer of Research, 11, 1434–40.

    Article  CAS  Google Scholar 

  149. Cohen, E. E. W., Davis, D. W., Karrison, T. G., Seiwert, T. Y., Wong, S. J., Nattam, S., 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 Oncology, 10, 247–57. doi:10.1016/S1470-2045(09)70002-6.

    Article  CAS  PubMed  Google Scholar 

  150. Argiris, A., Karamouzis, M. V., Gooding, W. E., Branstetter, B. F., Zhong, S., Raez, L. E., et al. (2011). Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 29, 1140–5. doi:10.1200/JCO.2010.33.3591.

    Article  CAS  Google Scholar 

  151. Argiris, A., Kotsakis, A. P., Hoang, T., Worden, F. P., Savvides, P., Gibson, M. K., et al. (2013). Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Annals of Oncology. Official Journal of European Society of Medical Oncology ESMO, 24, 220–5. doi:10.1093/annonc/mds245.

    Article  CAS  Google Scholar 

  152. Dorsey, K., & Agulnik, M. (2013). Promising new molecular targeted therapies in head and neck cancer. Drugs, 73, 315–25. doi:10.1007/s40265-013-0025-3.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padua, Padova, Italy

    Simonetta Ausoni

  2. Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Regional Hospital, Treviso, Italy

    Paolo Boscolo-Rizzo & Maria Cristina Da Mosto

  3. Laboratory of Epithelial Cancer Biology, Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, USA

    Bhuvanesh Singh

  4. Department of Otorhinolaryngology, Head and Neck Surgery, Cattinara Hospital, Trieste, Italy

    Giacomo Spinato & Giancarlo Tirelli

  5. Department of Otorhinolaryngology, Head and Neck Surgery, Dell’Angelo Hospital, Mestre, Venezia, Italy

    Roberto Spinato

  6. Department of Medical Oncology, Mirano Hospital, Local Health Unit 13, Mirano, Venezia, Italy

    Giuseppe Azzarello

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  1. Simonetta Ausoni
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Simonetta Ausoni and Paolo Boscolo-Rizzo are equally first authors

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Ausoni, S., Boscolo-Rizzo, P., Singh, B. et al. Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives. Cancer Metastasis Rev 35, 413–426 (2016). https://doi.org/10.1007/s10555-016-9625-1

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