Human epidermal growth factor receptor 3 in head and neck squamous cell carcinomas

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs. HER3 is a significant factor in HNSCC treatment resistance. Indeed, HER3 is a major mechanism described for cetuximab resistance because of modification of epidermal growth factor receptor (EGFR) internalization and by phosphotidylinositol‐3‐kinase (PI3K)/AKT signaling pathway activation. HER3 also affects resistance to tyrosine kinase inhibitors (TKIs) and thereby promotes treatment escape and radiotherapy resistance by activation of the survival signaling pathway. To counteract this, pharmacologic inhibitors of HER3 are currently in development and could significantly improve HNSCC treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E2412–E2418, 2016     

Targeting epidermal growth factor receptor in head and neck cancer

It is well known that growth factors play an important role in normal cell proliferation by means of stimulation of growth factor receptors located on the surface of cells. Tumor cells express high levels of growth factor receptors that can theoretically serve as therapeutic targets in cancer treatment. Tyrosine kinase (type 1) growth factor receptors include the family of erbB receptors. The most extensively studied receptor in the erbB family is the human epidermal growth factor receptor (EGFR), also known as erbB1. Studies have shown that overexpression of EGFR is involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). Blocking this receptor in HNSCC cell lines and animal models inhibits tumor growth. Strategies have been developed to target EGFR, including monoclonal antibodies, tyrosine kinase-specific inhibitors, ligand-linked immunotoxins, and antisense approaches. Laboratory studies and clinical trials are under way to explore the safety and efficacy of these various approaches in a variety of cancers, including HNSCC. Preliminary results from early phase clinical trials are encouraging and may lead to the incorporation of these EGFR targeting strategies into the management of HNSCC.     

Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications

Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)‐related tumors has shown a significant increase, and HPV‐related tumors show distinctive features if compared with the HPV‐negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol‐3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies. © 2015 Wiley Periodicals, Inc. Head Neck 37: 763–770, 2015     

Emerging perspectives in epidermal growth factor receptor targeting in head and neck cancer

The epidermal growth factor receptor (EGFR) has been shown to be a promising therapeutic target in head and neck cancer. Cetuximab, a monoclonal antibody against EGFR, has been approved in the United States for use with radiotherapy for head and neck squamous cell carcinoma. However, the role of EGFR targeting agents in other therapeutic modalities, such as combined chemoradiotherapy or induction chemotherapy, remains to be defined. Although results from several clinical trials have demonstrated the therapeutic potentials of EGFR targeting agents in these settings, further studies are necessary before definitive conclusions can be made. The concurrent targeting of EGFR along with other pathways important in carcinogenesis may hold significant therapeutic potential. In particular, several clinical trials are studying the effects of combining agents that target the vascular endothelial growth factor with EGFR inhibitors. Last, studies are ongoing to elucidate the predictive and correlative biomarkers in anti-EGFR therapy to allow for proper patient selection. In the case of cetuximab, these correlative biomarkers may include elements of the immune system in addition to the signal transduction proteins involved in EGFR pathway.     

Molecular mediators of metastasis in head and neck squamous cell carcinoma

BACKGROUND: The presence of regional metastasis in patients with head and neck squamous cell carcinoma (HNSCC) is a common and adverse event associated with poor prognosis and high mortality. Although significant improvements in standard therapies have increased the efficacy of local tumor management, the high incidence of tumor recurrence has resulted in limited improvements in overall survival rates. Understanding the molecular mechanisms that mediate HNSCC invasion and metastasis may enable identification of novel therapeutic targets for the prevention and management of tumor dissemination. METHODS: A literature review was performed. RESULTS: Several biologic mediators and mechanisms that have been implicated in HNSCC metastasis, such as cell adhesion molecules, proteolytic enzymes, growth factor signaling, metastasis suppressor genes, and chemokine receptors were reviewed. CONCLUSIONS: Prevention of HNSCC metastasis is an important clinical objective that requires an increased understanding of the molecular mechanisms of tumor invasion and dissemination.     

Endothelial growth factor receptor inhibitors in recurrent metastatic cancer of the head and neck

Targeted therapy has become an important new class of therapeutic agents used in squamous cell carcinoma of the head and neck (SCCHN). Among them epidermal growth factor receptor (EGFR) inhibitors have been studied the most. Today, two classes of EGFR inhibitors are routinely used in the clinic; anti‐EGFR monoclonal antibodies and small‐molecule inhibitors of the EGFR tyrosine kinase activity. These agents have been used clinically in the recurrent metastatic (R/M) settings but only cetuximab has reached a regulatory approval. Current research is focused on innovative compound design, predictive biomarker discovery, and combination strategies in order to overcome resistance. Efforts should also be focused on endpoints other than overall survival, which is the current gold standard, such as surrogate endpoints. This article summarizes the clinical evidence of the anticancer activity of EGFR inhibitors in patients with R/M SCCHN, and analyzes the current, controversial clinical issues with respect to their interpretation. © 2015 Wiley Periodicals, Inc. Head Neck 38 : E2221–E2228, 2016     

Telomerase as an independent prognostic factor in head and neck squamous cell carcinoma

BACKGROUND: Telomerase activity has been found to be associated with many cancers, including head and neck squamous cell carcinoma (HNSCC). We examined the association of telomerase activity with the clinical outcome of patients with HNSCC. METHODS: A PCR-based enzyme immunoassay method was used to measure telomerase activity in 217 matched (grossly normal and cancerous) tissues from patients with HNSCC. Pearson chi-square test was used to analyze the correlation of telomerase activity with clinicopathologic parameters. Kaplan-Meier method and Cox logistic regression model were used for prognostic analysis. RESULTS: Of the 217 tissues assayed, 4.1% of the normal and 63.3% of the cancer tissues had high levels of telomerase activity. Telomerase activity was shown to be statistically correlated with extracapsule spreading (ECS) of lymph nodes (p =.005) and overall survival (p =.003). On multivariant analysis, overall stage (p =.007), tumor depth (p =.045), and telomerase activity (p =.008) showed independent variables associated with poor survival. CONCLUSIONS: Telomerase activity has been shown to be an independent prognostic factor for survival in cases of HNSCC. Telomerase may be a potential molecular target for clinical use in prognostication and therapy in cases of the disease.