TREATMENT OF HEAD AND NECK SQUAMOUS CELL CARCINOMA ACCORDING ON THE SPECIFIC MOLECULAR FEATURES OF THE TUMOR (A LITERATURE REVIEW)

Despite the achieved progress in radiotherapy, chemotherapy, and surgery, head and neck squamous cell carcinoma (HNSCC) still remains the sixth most common cause of death from cancer worldwide. The division of HNSCC into 2 large groups with different survival rates is a significant achievement made during the last decades in cancer research and treatment of head and neck cancer. In 45 % – 90 % of cases, oropharyngeal squamous cell carcinoma is presumably associated with human papillomavirus (HPV). A recent whole-exome sequencing study on HNSCC helped to develop new principles of treatment that will allow to increase the effectiveness of conventional therapy. The study demonstrated that inactivating mutations in the p53 gene trigger carcinogenesis. The majority of tumors have such mutations that inactivate the p53 tumor suppressor gene. According to the results of sequencing, HPV-positive and HPV-negative tumors have completely different mutation profiles. Intratumoral heterogeneity should be taken into account when implementing new treatment approaches. We present an overview of studies published between 1989 and 2014. Current review briefly describes molecular mechanisms of carcinogenesis in HNSCC in the light of genetic and biochemical features of the tumor, paying particular attention to the most significant scientific achievements in this field. Moreover, we outline the advancements of wholeexome sequencing in HNSCC and give an overview of recent studies devoted to new therapeutic approaches. The process of carcinogenesis in HNSCC is often initiated by tumor suppressors. In this case, the development of target-based drugs is problematic. Target therapy focused on the ways of tumor growth suppression is a much more serious challenge than inhibition of oncogenic signals, because it requires reactivation of tumor suppressors and restoration of their functions, which is more difficult than conventional chemical and biological blockage. Poor survival of patients with HNSCC, which is usually associated with a small size of recurrent tumors, their latent growth, and localization in various anatomical areas, shows that there is an urgent need for developing new therapeutic approaches for the disease. 

The study was aimed to analyze specific molecular features of head and neck tumors and to explore the opportunities of providing personalized care for these patients.

1. Globocan 2012. Estimated cancer incidence, mortality and prevalence worldwide in 2012. International Agency for Research on Cancer. World Health Organisation. Available at: http:// globocan.iarc.fr/pages/fact_sheets_cancer. aspx.

2. Rothenberg S.M., Ellisen L.W. The molecular pathogenesis of head and neck squamous cell carcinoma. Jnl of Clin Invest 2012;122(6):1951–7. DOI: 10.1172/ JCI59889. PMID: 22833868.

3. Machiels J.P., Lambrecht M., Hanin F.X. et al. Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep 2014;6:44. DOI: 10.12703/P6-44. PMID: 24991421.

4. National Cancer Institute Head and Neck Cancer, 2014. Available at: https://www. cancer.gov/types/head-and-neck/patient/ oropharyngeal-treatmentpdq#section/_48.

5. Bonilla-Velez J., Mroz E.A., Hammon R.J. et al. Impact of human papillomavirus on oropharyngeal cancer biology and response to therapy: implications for treatment. Otolaryngol Clin North Am 2013;46(4):521–43. DOI: 10.1016/j. otc.2013.04.009. PMID: 23910468.

6. Joseph A.W., D'Souza G. Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol Clin North Am 2012;45(4):739–64. DOI: 10.1016/S14702045(10)70017-6. PMID: 20451455.

7. Marur S., D'Souza G., Westra W.H., Forastiere A.A. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010;11(8):781– 9. DOI: 10.1016/S1470-2045(10)70017-6. PMID: 20451455.

8. Nigro J.M., Baker S.J., Preisinger A.C. et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989;342(6250):705–8. DOI: 10.1038/342705a0. PMID: 2531845.

9. Gasco M., Crook T. The p53 network in head and neck cancer. Oral Oncol 2003;39(3):222–31. PMID: 12618194.

10. Somers K.D., Merrick M.A., Lopez M.E. et al. Frequent p53 mutations in head and neck cancer. Cancer Res 1992;52(21):5997–6000. Available at: http://cancerres.aacrjournals.org/ content/52/21/5997. PMID: 1394225.

11. Ohnishi K., Ota I., Takahashi A., Yane K. et al. Transfection of mutant p53 gene depresses X-ray-or CDDP-induced apoptosis in a human squamous cell carcinoma of the head and neck. Apoptosis 2002;7(4):367–72. PMID: 12101396.

12. Stransky N., Egloff A.M., Tward A.D. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333(6046):1157–60. PMID: 1394225.

13. Cancer Genome Atlas. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015; 517(7536):576–82. DOI: 10.1038/ nature14129. PMID: 25631445.

14. Tassone P., Old M., Teknos T.N. et al. p53-based therapeutics for head and neck squamous cell carcinoma. Oral Oncol 2013;49(8):733–7. DOI: 10.1016/j.oraloncology.2013.03.447. PMID: 23623836.

15. Qiu W., Schonleben F., Li X. et al. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett 2007;245(1– 2):163–70. DOI: 10.1016/j. canlet.2006.01.003. PMID: 16478646.

16. Han G., Lu S.L., Li A.G. et al. Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 2005;115(7):1714–23. DOI: 10.1172/JCI24399. PMID: 15937546.

17. Nagaraj N.S., Datta P.K.. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs 2010;19(1):77–91. DOI: 10.1517/13543780903382609. PMID: 20001556.

18. Doody R.S., Raman R., Farlow M. et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013;369(4):341–50. DOI: 10.1056/NEJMoa1210951. PMID: 23883379.

19. Morris L.G., Kaufman A.M., Gong Y. et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 2013;45(3):253–61. DOI: 10.1038/ ng.2538. PMID: 23354438.

20. Nishikawa Y., Miyazaki T., Nakashiro K. et al. Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin. Oncol Rep 2011;26(3):587– 92. DOI: 10.3892/or.2011.1324. PMID: 21617878.

21. Jerby-Arnon L., Pfetzer N., Waldman Y.Y. et al. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality. Cell 2014;158(5):1199–209. DOI: 10.1016/j. cell.2014.07.027. PMID: 25171417.

22. McLornan D.P., List A., Mufti G.J. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 2014;371(18):1725–35. DOI: 10.1056/NEJMra1407390. PMID: 25354106.

23. Martin S.A., McCabe N., Mullarkey M. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH or MLH1. Cancer Cell 2010;17:235–48. DOI: 10.1016/j. ccr.2009.12.046. PMID: 20227038.

24. Martin S.A., McCarthy A., Barber L.J. et al. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol Med 2009;1:323–37. DOI: 10.1002/ emmm.200900040.

25. Puram S.V., Rocco J.W. Molecular Aspects of Head and Neck Cancer Therapy/ Hematol Oncol Clin North Am 2015; 29(6): 971–92. DOI: http://dx.doi. org/10.1016/j.hoc.2015.07.003. PMID: 20049736.

26. Wang X., Simon R. Identification of potential synthetic lethal genes to p53 using a computational biology approach. BMC Med Genomics 2013;6:30. DOI: 10.1186/1755-8794-6-30.

27. Kalyankrishna S., Grandis J.R. Epidermal growth factor biology in head and neck cancer. J Clin Oncol 2006;24:2666–72. DOI: 10.1186/1755-8794-6-30. PMID: 24025726.

28. Ang K.K., Zhang Q., Rosenthal D.I., Nguyen-Tan P.F. et al. 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. J Clin Oncol 2014;32(27):2940–50. DOI: 10.1200/ JCO.2013.53.5633. PMID: 25154822.

29. Anderson J.A., Irish J.C., McLachlin C.M. et al. H-ras oncogene mutation and human papillomavirus infection in oral carcinomas. Arch Otolaryngol Head Neck Surg. 1994;120(7):755–60. PMID: 7912510.

30. Rocco J.W., Li D., Liggett W.H. et al. p16INK4A adenovirus-mediated gene therapy for human head and neck squamous cell cancer. Clin Cancer Res. 1998;4(7):1697–704. PMID: 9676844.

31. Grønhøj Larsen C., Gyldenløve M., Jensen D.H. et al. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review. Br J Cancer 2014;110(6):1587–94. DOI: 10.1038/bjc.2014.42. PMID: 24518594.

32. Lewis J.S., Jr. p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 2012;6(1):75–82. DOI: 10.1007/s12105012-0369-0. PMID: 22782226.

33. Spanos W.C., Nowicki P., Lee D.W. et al. Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol Head Neck Surg 2009;135(11):1137–46. DOI: 10.1001/ archoto.2009.159. PMID: 19917928.

34. el-Naggar A.K., Hurr K., Luna M.A. et al. Intratumoral genetic heterogeneity in primary head and neck squamous carcinoma using microsatellite markers. Diagn Mol Pathol. 1997;6(6):305–8. PMID: 9559289.

35. Götte K., Schäfer C., Riedel F. et al. Intratumoral genomic heterogeneity in primary head and neck cancer and corresponding metastases detected by dual-FISH. Oncol Rep 2004;11(1): 17–23. PMID: 14654897.

36. Mroz E.A., Tward A.D., Pickering C.R. et al. High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer 2013;119(16):3034–42. DOI: 10.1002/ cncr.28150. PMID: 23696076.

37. Sethi N., Wright A., Wood H. et al. MicroRNAs and head and neck cancer: reviewing the first decade of research. Eur J Cancer 2014;50(15):2619–35. DOI: 10.1016/j.ejca.2014.07.012. PMID: 25103455.

38. Cao P., Zhou L., Zhang J. et al. Comprehensive expression profiling of microRNAs in laryngeal squamous cell carcinoma. Head Neck 2013;35:720–8. DOI: 10.1002/hed.23011. PMID: 22605671.

39. Avissar M., Christensen B.C., Kelsey K.T. et al. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res 2009;15:2850–5. DOI: 10.1158/10780432.CCR-08-3131. PMID: 19351747.

40. Yan B., Fu Q., Lai L. et al. Downregulation of microRNA 99a in oral squamous cell carcinomas contributes to the growth and survival of oral cancer cells. Mol Med Rep 2012;6:675–81. DOI: 10.3892/ mmr.2012.971. PMID: 22751686.

41. Le J.M., Squarize C.H., Castilho R.M. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014;6(5):511–25. DOI: 10.4252/wjsc. v6.i5.511. PMID: 25426249.

42. Almeida L.O., Abrahao A.C., RosselliMurai L.K. et al. NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC). FEBS Open Bio 2014;4:96– 104. DOI: 10.1016/j.fob.2013.12.003. PMID: 24490130.

43. Giudice F.S., Pinto D.S., Jr., Nör J.E. et al. Inhibition of histone deacetylase impacts cancer stem cells and induces epithelial-mesenchyme transition of head and neck cancer. PLoS One 2013;8(3). DOI: 10.1371/journal.pone.0058672. PMID: 23527004.

44. Haigentz M., Kim M., Sarta C. et al. Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncol 2012;48(12):1281–8. DOI: 10.1016/j.oraloncology.2012.05.024. PMID: 22748449.