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Application of Molecular Targeted Therapies in the Treatment of Head and Neck Squamous Cell Carcinoma (Review)

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Application of Molecular Targeted Therapies in the Treatment of Head and Neck Squamous Cell Carcinoma (Review) ONCOLOGY LETTERS 15: 7497-7505, 2018 Application of molecular targeted therapies in the treatment of head and neck squamous cell carcinoma (Review) PAULINA KOZAKIEWICZ and LUDMIŁA GRZYBOWSKA‑SZATKOWSKA Department of Oncology, Medical University of Lublin, 20‑90 Lublin, Poland Received November 21, 2017; Accepted January 31, 2018 DOI: 10.3892/ol.2018.8300 Abstract. Despite the development of standard therapies, 1. Introduction including surgery, radiotherapy and chemotherapy, survival rates for head and neck squamous cell carcinoma (HNSCC) Among head and neck cancers (HNC), the majority, ≤90%, have not changed significantly over the past three decades. comprise of mutations originating in the squamous epithelium Complete recovery is achieved in <50% of patients. The treat- of the upper aerodigestive tract (1). Head and neck squamous ment of advanced HNSCC frequently requires multimodality cell carcinoma (HNSCC) is the seventh most frequently therapy and involves significant toxicity. The promising, occurring and the ninth most fatal cancer (1). Standard novel treatment option for patients with HNSCC is molec- therapies used for treatment of HNSCC have achieved a ular‑targeted therapies. The best known targeted therapies consistent five‑year survival rate ranging from 40‑50% in the include: Epidermal growth factor receptor (EGFR) mono- past three decades (2). Treatment for the early stage of this clonal antibodies (cetuximab, panitumumab, zalutumumab disease is a single therapeutic method, including surgery or and nimotuzumab), EGFR tyrosine kinase inhibitors (gefi- radiotherapy (2,3). Cure rates of >90 and 70% have been tinib, erlotinib, lapatinib, afatinib and dacomitinib), vascular achieved for stage I and II, respectively (3,4). The radical treat- endothelial growth factor (VEGF) inhibitor (bevacizumab) ment of patients with locally advanced cancer in stage III or or vascular endothelial growth factor receptor (VEGFR) IV requires multimodality therapy. At these stages, a surgical inhibitors (sorafenib, sunitinib and vandetanib) and inhibitors treatment is complemented with radiotherapy or chemoradio- of phosphatidylinositol 3-kinase/serine/threonine-specific therapy, depending on the risk factors for a relapse including: protein kinase/mammalian target of rapamycin. There are also Dubious margin of healthy tissue; poorly differentiated (G3) various inhibitors of other pathways and targets, which are cancer; and feature pT4 (advanced local disease) or metastases promising and require evaluation in further studies. in the regional lymph nodes (5,6). In stage III and IV it is also possible to apply an organ conserving therapy, such as chemo-radiotherapy or targeted therapy using monoclonal Contents antibodies in combination with radiotherapy (6,7); however, the treatment effects are not as satisfactory, compared with 1. Introduction the early stages of the disease. Tumor recurrence within two 2. Epidermal growth factor receptor years was ~0% in patients who were treated for a locally 3. Tyrosine kinase inhibitors advanced HNC (8). In these cases, the possibility of treatment 4. Vascular endothelial growth factor with salvage surgery or re‑irradiation is limited (8). The use of 5. The PI3K/AKT/mTOR pathway chemotherapy in patients with recurrent or metastatic changes 6. The PD results in response rates ranging from 10-35% and a median 7. Other potential targeted therapies survival of 6‑12 months (9). Concurrent radiochemotherapy in 8. Conclusion the treatment of HNSCC is complicated due to the occurrence of side effects, including mucositis, dermatitits and dysphagia. The treatment is frequently accompanied by leukopenia and thrombocytopenia, which increases the risk of infection or bleeding (4). Following the treatment, the quality of life dete- Correspondence to: Miss Paulina Kozakiewicz, Department riorated due to late complications including: Sensorineural of Oncology, Medical University of Lublin, Jaczewskiego 7, hearing loss; polyneuropathy caused by chemotherapy 20‑90 Lublin, Poland E‑mail: [email protected] or permanent xerostomia; and impaired swallowing (4). Unsatisfactory outcomes of the HNC treatment using standard Key words: head and neck cancer, targeted therapies, epidermal methods with high toxicity warrant a search for novel thera- growth factor receptor, vascular endothelial growth factor receptor, peutic options. The search for novel therapies is justified by tyrosine kinase inhibitors, programmed death receptor achievements of genetics and molecular biology, which have initiated the development of targeted cancer therapies (10). These treatments have already been successfully used in the 7498 KOZAKIEWICZ and GRZYBOWSKA‑SZATKOWSKA: MOLECULAR TARGETED THERAPIES IN HNC treatment of other solid tumor types, including colorectal or route (14). Further research on the EGFR gene is required. Due lung cancer (10). The action of targeted drugs consist of inac- to the individual variable response to treatment with targeted tivating specific target molecules required for oncogenesis and therapies, there are various described mutations and polymor- tumor growth (11). phisms of the EGFR gene, which may be a predictive factor for In the present review, a description of the currently most cancer therapy (19). promising and well-known molecular targeting strategies Cetuximab is a chimeric human immunoglobulin G1 used in the treatment of advanced head and neck cancers were antibody that binds to domain III of the extracellular region produced. These treatments target (Table I): i) Epidermal of EGFR (12,20). Its effect on tumor cells is based on three growth factor receptor (EGFR), ErbB1; ii) vascular endo- different underlying mechanisms, which lead to the induction of thelial growth factor (VEGF) and vascular endothelial apoptosis, inhibition of proliferation, angiogenesis and increase growth factor receptor (VEGFR); iii) intracellular signaling in the response to chemo‑ and radiotherapy (20). Cetuximab pathway components associated with the phosphatidylino- inhibits the phosphorylation of EGFR and transmission of sitol 3‑kinase (PI3K)/serine/threonine‑specific protein signals to the cell, due to it preventing the attachment of other kinase (AKT)/mammalian target of rapamycin (mTOR); and ligands via its direct binding to the receptor. Furthermore, it iv) programmed death receptor 1 (PD‑1). Other hotspots for induces ADCC, which leads to the removal of coated cells targeted therapies in the cells of HNSCC are sought after. with cetuximab (21). The result of the connection between cetuximab and EGFR may also be the internalization and 2. Epidermal growth factor receptor reduction of the amount of cetuximab on the cell surface (21). The Agency for Food and Drug Administration (FDA) EGFR, in other words ErbB1 or Her1 is the most well‑known approved the use of cetuximab in cancer therapy in 2004 for and described cancer drug target. EGFR is a transmembrane the treatment of EGFR-expressing metastatic colon cancer protein that belongs to the ErbB/HER family of receptor tyro- resistant to irinotecan‑based chemotherapy (22). After 4 years, sine kinases (RTK) activity (12). Extracellular signals, which it in 2006 the FDA approved cetuximab in combination with transduces, are altered into intracellular responses, influencing radiotherapy for the treatment of locally advanced HNSCC on cell proliferation, apoptosis, angiogenesis and the capacity of the basis of data were obtained from a multicenter phase III tumor cells to metastasize (12). Following binding the ligand clinical trial (23). It demonstrated a statistically significant [epidermal growth factor (EGF) or transforming growth improvement in median OS in case of using radiotherapy plus factor α (TGFα)], EGFR forms a homodimer or heterodimer cetuximab in comparison with radiation (49 and 29 months, with other members of the Erb family (ErbB2, ErbB3 and respectively) in the initially untreated patients with stages III ErbB4) and activates the downstream signaling through the and IV without distant metastases (23). mitogen‑activated protein kinases (MAPKs) cascade and the Vermorken et al (24) demonstrated an increase in median PI3K/AKT/mTOR pathway (13). This leads to the activation of OS by ~3 months and an increase in median progression‑free certain genes in the cell nucleus, which promote angiogenesis, survival (PFS) from 3.3 to 5.6 months in the group with the formation of metastases (13,14). EGFR overexpression can cetuximab and chemotherapy, compared with the group be determined in ~90% of HNSCC (8). It is considered to be a with chemotherapy alone in metastatic or recurrent HNSCC. negative prognostic factor that increases the size of the tumor, In 2008, based on the aforementioned trials, Cetuximab was reduces its radiosensitivity and increases the risk of its recur- approved by the FDA and European Medicines Agency, for rence (8). In multivariate analysis, it was demonstrated that locally advanced or metastatic HNSCC. Despite the improve- EGFR overexpression in patients with stages II‑IV HNSCC, ment in treatment results obtained following the application of treated with standard radiation therapy, was associated with cetuximab with radiotherapy in the aforementioned trial, the earlier relapse, reduced disease-free survival and overall addition of this monoclonal antibody to chemoradiotherapy survival (OS) (13,14). Higher expression of the EGFR receptor based on cisplatin in locally advanced HNSCC did not improve is observed in well and moderately differentiated
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