• Korean Journal of Head & Neck Oncology
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• v.37 no.2
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• pp.11-17
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• 2021

Head and neck cancer is the 6^th most frequently diagnosed solid tumor in the world. Alcohol consumption, smoking, and HPV infection are associated with the incidence of head and neck squamous cell carcinoma (HNSCC). Although a multidisciplinary approach is a key strategy for the treatment of locally advanced HNSCC, systemic therapy is the mainstream of recurrent or metastatic HNSCC treatment. Stage IV HNSCC has a relatively poor prognosis with median overall survival of around one year. There have been many clinical trials to investigate the efficacy of target agents in the treatment of HNSCC. In the HPV-negative HNSCC, TP53 and CDKN2A are the most commonly mutated genes. In the HPV-positive HNSCC, the PI3K pathway is frequently altered. EGFR, PI3K, cell cycle pathway, MET, HRAS, and IL6/JAK/STAT pathway are explored targets in HNSCC. In this study, we review the target pathways and agents under research. We also introduce here umbrella trials of recurrent or metastatic HNSCC conducted by the Korea Cancer Study Group. The combination of target agents with immune checkpoint inhibitors or cytotoxic chemotherapies would be a future step in the precision medicine of HNSCC treatment.

• Korean Journal of Head & Neck Oncology
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• v.21 no.2
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• pp.158-164
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• 2005

Purpose: The serine/threonine kinase Akt was described to inhibit apoptosis in cancer. This study was to examine the effect of Gleevec on head and neck squamous cell carcinoma(HNSCC) through the mechanism of Akt. Experimental Design: Gleevec was introduced into the HNSCC cell lines UMSCC10B, HN12 and HN30 in a range of concentrations. Cell viability was assessed by clonogenic survival analysis. Targets of Gleevec(PDGFR, c-Kit, and c-Abl) were evaluated by Western blot. HNSCC tissue samples were stained for PDGFR, c-Kit and phosphorylated Akt. Akt phosphorylation following Gleevec treatment was assessed using Western blot. Akt siRNA was used to as the positive control. Results: Colony forming efficiency decreased with an increase in concentration of Gleevec. Expressions of PDGFR, c-Kit, and c-Abl were observed in HNSCC cells. Immunohistochemistry confirmed high expression of PDGFR, c-Kit, and p-Akt in human HNSCC tissues. Akt kinase activity was significantly inhibited with increasing concentration of Gleevec in HNSCC cells, and near complete dephosphorylation of Akt was observed at $6{\mu}M$ of Gleevec in the UMSCC10B and HN30 cell lines. Conclusions: Gleevec at clinically comparable concentrations caused a dose dependant decrease in HNSCC survival. The decreased cell survival was related to the inhibition of Akt kinase activity and dephosphorylation of Akt. Akt signaling pathway may be a relevant target for Gleevec in treating HNSCC.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7031-7038
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• 2015

Background: Arginine may play important roles in tumor progression by providing ornithine for polyamine biosynthesis, required for cell growth. The aim of this work was to determine the expression of arginine metabolic pathway enzymes in head and neck squamous cell carcinoma (HNSCC) in northeast India. Materials and Methods: The expressions of arginase isoforms (ARG1 and ARG2), ornithine aminotransferase (OAT) and ornithine decarboxylase (ODC) were examined in fifty paired HNSCC and adjacent non-tumor tissues by immunohistochemistry. Immunocytochemistry, semiquantitative reverse transcription sq-PCR and quantitative real-time qPCR were used to assess protein and mRNA expressions in peripheral blood of fifty HNSCC patients and hundred controls. Results: ARG1 and ODC protein and mRNA were strongly expressed in peripheral blood from HNSCC patients. No ARG2 expression was observed. In vivo, expression of ARG1, ARG2 and ODC was significantly higher in tumor than in non-tumor tissues. Most tumors expressed low levels of OAT, with no difference in tissues or blood, compared to controls. The absolute extent of maximal ARG1 upregulation with qPCR showed 6.23 fold increase in HNSCC. Conclusions: These findings strongly suggest that in HNSCCs, the ARG1 pathway is stimulated leading to the formation of polyamines as indicated by higher ODC expression, which promote tumor growth.

• Korean Journal of Head & Neck Oncology
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• v.18 no.1
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• pp.18-22
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• 2002

Background and Objectives: The expression of telomerase, a ribonucleoprotein complex, has been detected in tissues from many human cancers, but not in the majority of normal tissues except germ cell. It is believed that the activation of telomerase is linked to celluar immortality and may playa role in tumorigenesis. Human telomerase reverse transcriptase (hTERT) has been identified as a putative catalytic subunit of human telomerase and its expression is closely correlated with telomease activity. We studied the expression of hTERT in head and neck squamous cell carcinoma (HNSCC) and resection margin by immunohistochemistry for hTERT and evaluate the correlation between hTERT expression and clinical data in HNSCC. Materials and Methods: We performed a immunohistochemistry in 17 cases of HNSCC and 10 cases of resection margins, histologically normal. The correlations between the hTERT expression and the clinical data in HNSCC were analyzed. Result: hTERT immunoreactivities were detected in 14 of 17 (82.4%) HNSCC, 1 of 10 (10%) resection margin. No correlation was observed between clinical data and hTERT expression in HNSCC. Conclusion: hTERT is activated in HNSCC and its expression is independent from clinical data of patients.

• Korean Journal of Head & Neck Oncology
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• v.33 no.1
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• pp.1-5
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• 2017

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high morbidity and mortality. Immune surveillance is well recognized as an important mechanism to prevent development or progression of HNSCC. HNSCC can escape the immune system through multiple mechanisms including development of tolerance in T cells and inhibition of T-cell-related pathways, generally referred to as checkpoint inhibitors. Recent clinical trials have demonstrated a clear advantage in advanced HNSCC patients treated with immune checkpoint blockade. Right at the front of the new era of immunotherapy, we will review current knowledge of immune escape mechanisms and clinical implication for HNSCC.

• Korean Journal of Head & Neck Oncology
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• v.33 no.1
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• pp.7-13
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• 2017

Despite improved treatment outcomes of locally advanced disease over the last 2 decades, the survival of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains dismal. There is a clear need for development of novel therapeutic strategies for recurrent and/or metastatic HNSCC. Recent advances in understanding tumor immunology have been directly and rapidly translated into clinical success of T cell-directed immunotherapeutic approach in the treatment of several types of solid cancers. Among them, impact of immune checkpoint inhibition using neutralizing antibodies is the most striking. A variety of immunotherapeutic strategies targeting T cells have been also studied in HNSCC, especially in recurrent and/or metastatic setting even with significant survival benefit. The present article reviews the basic concept of T cell-directed immunotherapy and the current status of such approaches in the treatment of HNSCC.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2891-2896
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• 2012

Background: HER2/neu, a member of EGFR family, is over expressed in some tumors. The purpose of this study was to determine the salivary level and tissue expression of HER2/neu in patients with head and neck squamous cell carcinoma (HNSCC) and any correlation with clinicopathologic parameters. Methods: An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the salivary level and immunohistochemistry (IHC) to assess tissue expression of HER2/neu in 28 patients with HNSCC and 25 healthy controls. Results: The salivary levels of HER2/neu in HNSCC patients was not significantly higher than in the healthy controls (p>0.005). There was no apparent correlation in salivary HER2/neu level with clinicopathological features such as age, sex, grade, tumor size and nodal status. All HNSCC specimens were positive (membranous or/and cytoplasmic) for HER2/neu, except one sample. Only one HNSCC specimen was stained in cytoplasm purely. All control specimens were membranous and cytoplasmic positive for HER2/neu. There was a significant difference between cytoplasmic staining in case and control groups (p-value<0.05). Conclusion: In our cases, no overexpression of HER2/neu was observed. Thus, our findings suggested that the use of Her-2 as a salivary marker of HNSCC cannot be recommended.

• Radiation Oncology Journal
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• v.38 no.2
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• pp.99-108
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• 2020

Purpose: The probability of recurrence of cancer after adjuvant or definitive radiotherapy in patients with human papillomavirus-negative (HPV(-)) head and neck squamous cell carcinoma (HNSCC) varies for each patient. This study aimed to identify and validate radiation sensitivity signature (RSS) of patients with HPV(-) HNSCC to predict the recurrence of cancer after radiotherapy. Materials and Methods: Clonogenic survival assays were performed to assess radiosensitivity in 14 HNSCC cell lines. We identified genes closely correlated with radiosensitivity and validated them in The Cancer Genome Atlas (TCGA) cohort. The validated RSS were analyzed by ingenuity pathway analysis (IPA) to identify canonical pathways, upstream regulators, diseases and functions, and gene networks related to radiosensitive genes in HPV(-) HNSCC. Results: The survival fraction of 14 HNSCC cell lines after exposure to 2 Gy of radiation ranged from 48% to 72%. Six genes were positively correlated and 35 genes were negatively correlated with radioresistance, respectively. RSS was validated in the HPV(-) TCGA HNSCC cohort (n = 203), and recurrence-free survival (RFS) rate was found to be significantly lower in the radioresistant group than in the radiosensitive group (p = 0.035). Cell death and survival, cell-to-cell signaling, and cellular movement were significantly enriched in RSS, and RSSs were highly correlated with each other. Conclusion: We derived a HPV(-) HNSCC-specific RSS and validated it in an independent cohort. The outcome of adjuvant or definitive radiotherapy in HPV(-) patients with HNSCC can be predicted by analyzing their RSS, which might help in establishing a personalized therapeutic plan.

• Korean Journal of Head & Neck Oncology
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• v.17 no.2
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• pp.169-173
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• 2001

Objectives: The p53 tumor suppressor gene encodes a nuclear transcription factor that is critical regulator of cell growth and proliferation through its action in cell-cycle checkpoint control. The wide variety of stressful stmuli which include DNA damage, hypoxia, heat shock, metabolic changes activate the p53 protein, which in turn drives a series of events that culminate either in cell cycle arrest or apoptosis. Mutations of the p53 gene is the most common genetic alteration in human cancer. This gene is altered in approximately 40-60% of head and neck cancers. Whereas the wild-type form of the p53 protein plays a central role in cell-cycle control in response to DNA damage, most of the mutant forms are unable to do so. The high levels of p53 protein expression in tissues are related to the increased cellular proliferative activity and may be associated with the poor clinical outcome. To determine whether the expression of the p53 protein has prognostic significance and is associated with patterns of treatment failure in head and neck squamous cell carcinoma (HNSCC), We analyzed p53 overexpression in 40 cases of HNSCC. Materials and Methods: Immunohistochemical analysis with a monoclonal antibody (DO7) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 40 HNSCC. We evaluated p53 protein expression and analyzed the relationship between the p53 overexpression and age, sex, primary tumor site, stage, survival rate, recurrence. All reported P values resulted from two-sided statistical tests. Results: Overexpression of p53 was detected in 20 cases(50%) among 40 cases of HNSCC. The p53 overexpression was not associated with age, sex, primary tumor site, stage, recurrence and survival rate. Conclusions: In our results, p53 was not significant prognostic factor in HNSCC. Based on many previous studies, It is evident that p53 has a certain role in tumorigenesis of HNSCC. So, the further study is needed to evaluate the prognostic significance of p53 in HNSCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6649-6655
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• 2014

Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.