Predictive and Prognostic Molecular Markers of Oral Cancers and Potential Therapeutic Agents Targeting These Markers
Shilpa Jain, Anil Goel, Arpita H Patel, Sarvatnida Shaikh
Keywords :
Epidermal growth factor receptor, Human papillomavirus, Molecular markers, Neurogenic locus notch homolog protein, Oral cavity cancer, p53
Citation Information :
Jain S, Goel A, Patel AH, Shaikh S. Predictive and Prognostic Molecular Markers of Oral Cancers and Potential Therapeutic Agents Targeting These Markers. Indian J Med Biochem 2024; 28 (3):82-90.
In the last two decades, there has been tremendous research in the field of oncogenesis at the molecular level. With the unveiling of various signaling pathways and molecular markers involved in oncogenesis, efforts are being made to develop therapeutic agents targeted at these molecular levels.
Oral cancers constitute 40% of all head and neck cancers and are major health concerns all over the world. The age-adjusted incidence rate for oral cancer is 4 per 1,00,000 population in males and 2 per 1,00,000 population in females worldwide with an overall 5-year survival rate of 50–60%.
About 30% of patients of oral cancer present with early-stage disease where surgery and/or radiotherapy can achieve cure rates of about 70–90%. However, the majority of patients present in locally advanced stages, where we have to use combined treatment modalities leading to more side effects and morbidity. The recurrence rate is also about 40–50% in advanced stages and there are limited treatment options available once the primary treatment modalities fail. Despite all the development in areas of genomics and proteomics of oncogenesis, there has not been a breakthrough in treatment modalities available or overall improvement in survival rates of such patients.
This review intends to highlight the genomic alterations and signaling pathways involved in oral cancers. The biomarkers which can be used as predictive and prognostic markers in oral cancers which can be potential therapeutic targets will also be discussed in this review. The findings of available studies obtained from a literature search will be comprehensibly presented in this review.
Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 2007;99:777–789. DOI: 10.1093/jnci/djk179.
Pande P, Soni S, Chakravarti N, et al. Prognostic impact of Ets-1 overexpression in betel and tobacco related oral cancer. Cancer Detect Prev 2001;25(5):496–501. PMID: 11718456.
Sharma DC. Betal quid and areca nut are carcinogenic without tobacco. Lancet Oncol 2003;4(10):587. DOI: 10.1016/s1470-2045(03) 01229-4.
RR Manon, Mayers JN, Harari PM. Oral cavity. In: Halperin EC, Wazer DE, Perez CA, Brady LW, editors. Principles and Practice of Radiation Oncology. 7th ed. Wolter Kluwer; 2019. pp. 3066–3149.
D'Souza G, Kreimer AR, Viscidi R, et al. Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer. N Engl J Med 2007;356:1944–1956. DOI: 10.1056/NEJMoa065497.
C Fakhry, H William, WS Li, et al. Improved survival of patients with human papillomavirus–positive head and neck squamous cell carcinoma in a prospective clinical trial. J Nat Cancer Inst 2008; 100(4): 261–269. DOI: 10.1093/jnci/djn011.
SS Prime, Thakker NS, Pring M, et al. A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma. Oral Oncol 2001;37(1):1–16. DOI: 10.1016/s1368-8375(00)00055-5.
Nalejska E, Maczynska E, Lewandowska MA. Prognostic & Predictive biomarkers: Tools in personalised Oncology. Mol Diagn Ther 2014;18: 273–284. DOI: 10.1007/s40291-013-0077-9.
Wondergem NE, Nijenhuis DNL, Poell JB, et al. At the crossroads of molecular biology and Immunology: Molecular pathways for immunological targeting of head and neck squamous cell carcinoma. Frontiers oral health 2021;2:1–9. DOI: 10.3389/froh.2021.647980.
Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000;408:307–310. DOI: 10.1038/35042675.
Brady CA, Jiang D, Mello SS, et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 2011;145: 571–583. DOI: 10.1016/j.cell.2011.03.035.
Satayanarayan A, Kaldis P. A dual of CDK2 in DNA damage response. Cell Div 2009;4:1–4. DOI: 10.1186/1747-1028-4-9.
Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002;2:103–112. DOI: 10.1016/s1535-6108(02)00102-2.
Peurala E, Koivunen P, Happasaari KM, et al. Prognostic significance and value of Cyclin D1, CDK4 and p16 in human breast cancer. Breast Cancer Res 2013;15:1–10. DOI: 10.1186/bcr3376.
Boyle JO, Hakim J, Koch W, et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 1993;53:4477–4480. PMID: 8402617.
Cabelguenne A, Blons H, de Waziers I, et al. p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: A prospective series. J Clin Oncol 2000;18:1465– 1473. DOI: 10.1200/JCO.2000.18.7.1465.
Hosmani J, Mushtaq S, Abullais SS, et al. Recombinant human adenovirus-p53 therapy for the treatment of oral leukoplakia and oral squamous cell carcinoma: A systematic review. Medicina 2021;57(5):438. DOI: 10.3390/medicina57050438.
Beck TN, Golemis EA. Genomic insights into head and neck cancer. Cancers Head Neck 2016;1:1–17. DOI: 10.1186/s41199-016-0003-z.
Riess C, Irmscher N, Salewski I. Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology? Cancer Metastasis Rev 2021;40,153–171. DOI: 10.1007/s10555-020-09940-4.
Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomark Prev 2005;14:467–475. DOI: 10.1158/1055-9965.EPI-04-0551.
Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24:736–747. DOI: 10.1200/JCO.2004.00.3335.
Nair S, Bonner JA, Bredel M. EGFR mutations in head and neck squamous cell carcinoma. Int J Mol Sci 2022;23(7):3818. DOI: 10.3390/ijms23073818.
Hynes NE, Lane HA. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341–354. DOI: 10.1038/nrc1609.
Lin SY, Makino K, Xia W, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 2001;3:802–808. DOI: 10.1038/ncb0901-802.
Zhu QG, Zhang SM, Ding XX, et al. Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies. Oncotarget 2017;8(34):57680–57692. DOI: 10.18632/oncotarget.17016.
Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007;25:2164–2170. DOI: 10.1200/JCO.2006.06.6605.
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;354:567–578. DOI: 10.1056/NEJMoa053422.
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359: 1116–1127. DOI: 10.1056/NEJMoa0802656.
Harrington K, Berrier A, Robinson M, et al. 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. Eur J Cancer 2013;49:1609–1618. DOI: 10.1016/j.ejca.2012.11.023.
Giralt J, Trigo J, Nuyts S, et al. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): A randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015;16(2):221–232. DOI: 10.1016/S1470-2045(14)71200-8.
Junlin Yi, Jin Yi Lang, Chenping Zhang, et al. Nimotuzumab in combination with intensity modulated radiotherapy improve survival in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): A multicenter-based real-world study. Journal of Clinical Oncology 2023;41:16_suppl, e18006-e18006.
Chen J, Cheng CS, Chen J, et al. Sorafenib for treating head and neck adenocarcinoma of unknown primary site: A case report. J Int Med Res 2020;48(11):1–9. DOI: 10.1177/0300060520964355.
Uppaluri R, Winkler AE, Lin T, et al. Biomarker and tumor responses of oral cavity squamous cell carcinoma to trametinib: A phase ii neoadjuvant window-of-opportunity clinical trial. Clin Cancer Res 2017;23(9):2186–2194. DOI: 10.1158/1078-0432.CCR-16-1469.
Nathan CO, Hayes DN, Karrison T, et al. A randomized multi-institutional phase ii trial of everolimus as adjuvant therapy in patients with locally advanced squamous cell cancer of the head and neck. Clin Cancer Res 2022;28(23):5040–5048. DOI: 10.1158/1078-0432.CCR-21-4290.
Ho AL, Brana I, Haddad R, et al. Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. J Clin Oncol 2021;39(17): 1856–1864. DOI: 10.1200/JCO.20.02903.
Sen M, Thomas SM, Kim S, et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: Implications for cancer therapy. Cancer Discov 2012;2(8):694–705. DOI: 10.1158/2159-8290.CD-12-0191.
Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333:1154–1157. DOI: 10.1126/science.1206923.
Dotto GP. Crosstalk of Notch with p53 and p63 in cancer growth control. Nat Rev Cancer 2009;9:587–595. DOI: 10.1038/nrc2675.
Talora C, Sgroi DC, Crum CP, et al. Specific down-modulation of Notch1 signalling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 2002;16:2252–2263. DOI: 10.1101/gad.988902.
Czerwonka A, Kałafut J, Nees M. Modulation of notch signaling by small-molecular compounds and its potential in anticancer studies. Cancers 2023; 15(18):456. DOI: 10.3390/cancers15184563.
Song, C, Zhang J, Xu C, et al. The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics. Inter J of Biol Sci 2023;19(16):5089–5103. DOI: 10.7150/ijbs.87334.
Engelman JA. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550–562. DOI: 10.1038/nrc2664.
Shi X, Wang J, Lei Y, Cong C, et al. Research progress on the PI3K/AkT signalling pathway in gynaecological Cancer. Mol Med Rep 2019;19: 4529–4535. DOI: 10.3892/mmr.2019.10121.
Janku F, Wheler JJ, Naing A, et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 2013;73:276–284. DOI: 10.1158/0008-5472.CAN-12-1726
Geiger JL, Bauman JE, Gibson MK, et al. Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head Neck 2016;38(12):1759–1764. DOI: 10.1002/hed.24501.
Fury MG, Lee NY, Sherman E, et al. A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2013;87(3):479–486. DOI: 10.1016/j.ijrobp.2013.06.2043.
Dongheon L, Sil E, Sung J, et al. Development of antibody-based c-Met inhibitors for targeted cancer therapy. Immunotargets Ther 2015;4:35–44. DOI: 10.2147/ITT.S37409.
Knowles LM, Stabile LP, Egloff AM, et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res 2009;15:3740–3750. DOI: 10.1158/1078-0432.CCR-08-3252.
Zhao D, Wang SH, Feng Y, et al. Intratumoral c-Met expression is associated with vascular endothelial growth factor C expression, lymphangiogenesis, and lymph node metastasis in oral squamous cell carcinoma: Implications for use as a prognostic marker. Hum Pathol 2011;42:1514–1523. DOI: 10.1016/j.humpath.2010.03.012.
Arnold L, Enders J, Thomas SM. Activated HGF-c-Met Axis in head and neck Cancer. Cancers 2017;12;9(12):169. DOI: 10.3390/cancers9120169.
Lüttich L, Besso MJ, Heiden S, et al. Tyrosine kinase c-MET as therapeutic target for radiosensitization of head and neck squamous cell carcinomas. Cancers 2021;13(8):1865. DOI: 10.3390/cancers13081865.
Xie J, Huang L, Lu Y-G, et al. Roles of the Wnt Signaling Pathway in Head and Neck Squamous Cell Carcinoma. Front Mol Biosci 2021;7:590912. DOI: 10.3389/fmolb.2020.590912.
Minde DP, Anvarian Z, Stefan GD, et al. Messing up disorder: How do missense mutations in the tumor suppressor protein APC lead to cancer? Mol Cancer 2011;10:1–9. DOI: 10.1186/1476-4598-10-101.
Zhao YY, Yu GT, Xiao T, et al. The notch signaling pathway in head and neck squamous cell carcinoma: A meta-analysis. Adv Clin Exp Med 2017;26:881–887. DOI: 10.17219/acem/64000.
Morris LG, Kaufman AM, Gong Y, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 2013;45:253–261. DOI: 10.1038/ng.2538.
Rodon, J, Argilés G, Connolly RM. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer 2021;125:28–37. DOI: 10.1038/s41416-021-01389-8.
Botticelli A, Cirillo A, Strigari L, et al. Anti PD-1 and Anti PD-L1 in head and neck cancer: A network analysis. Front Immunol 2021;12:1–9. DOI: 10.3389/fimmu.2021.705096.
Perri F, Ionna F, Longo F, et al. Immune response against head and neck cancer: Biological mechanisms and implication on therapy. Transl Oncol 2020;13(2):262–274. DOI: 10.1016/j.tranon.2019. 11.008.
Sousa LG, Ferrarotto R. Pembrolizumab in the first-line treatment of advanced head and neck cancer. Expert Rev Anticancer Ther 2021;21(12):1321–1331. DOI: 10.1080/14737140.2021.1996228.
Sato Y, Fukuda N, Wang X, et al. Efficacy of nivolumab for head and neck cancer patients with primary sites and histological subtypes excluded from the checkmate-141 trial. Cancer Manag Res 2020;12:4161–4168. DOI: 10.2147/CMAR.S249393.