Special Issue "Targeting Head and Neck Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editors

Prof. Dr. Michiel Wilhelmus Maria Van den Brekel
Website
Guest Editor
The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Interests: head and neck cancer; molecular biology; imaging; rehabilitation
Dr. Bhuvanesh Singh
Website
Guest Editor
Memorial Sloan-Kettering Cancer Center, Department of Surgery, New York, United States
Interests: head and neck cancer, molecular biology, translational medicine
Dr. Charlotte Zuur
Website
Guest Editor
Netherlands Cancer Institute, Amsterdam, The Netherlands
Interests: head and neck cancer, translational research, novel treatments

Special Issue Information

Dear colleagues,

Targeted therapies in head and neck cancer are crucial to personalizing treatment and improving outcomes. Genetic profiling of tumors has shown several subtypes, but currently only HPV-associated tumors are seen as a distinct entity. Also, subtypes with more DNA repair deficits, hypoxia, EMT, and other pathway aberrations have been identified. Unfortunately, this has not yet led to different treatment protocols. Chemotherapy and small molecules have so far not played an important role in the curative setting in head and neck cancer. However, in the palliative setting, especially in salivary gland cancer, more targeted therapies are becoming available, and in several basket trials genetic profiling is used to select the most optimal strategy. In the neoadjuvant setting, chemotherapy, targeted molecules, and immunotherapy are being explored. As radiosensitizers, so far only cisplatin and cetuximab are widely used, but no reliable biomarkers are used to predict a response. PARP inhibition has been shown to act as a strong radiosensitizer and is currently under investigation. A major issue is the lack of reliable biomarkers and in vitro systems to predict a response. In this issue, several aspects of targeted treatment will be covered. Researchers studying biomarkers, as well as model systems and trials using a targeted approach, are invited to submit manuscripts.

Prof. Dr. Michiel Wilhelmus Maria van den Brekel
Dr. Bhuvanesh Singh
Dr. Charlotte Zuur
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • targeted therapy
  • biomarkers
  • head and neck cancer
  • model systems
  • radiosensitizer
  • immunotherapy
  • pathway inhibition
  • salivary gland carcinoma
  • personalized medicine

Published Papers (20 papers)

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Open AccessArticle
Third Epidemiological Analysis of Nasopharyngeal Carcinoma in the Central Region of Japan from 2006 to 2015
Cancers 2019, 11(8), 1180; https://doi.org/10.3390/cancers11081180 - 15 Aug 2019
Abstract
The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in [...] Read more.
The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in the Chubu region in the central Japanese main island, with a population of around 22.66 million individuals. This study was designed in line with to two previous clinical studies into NPC conducted in the same area of Japan. We recruited NPC patients diagnosed in hospitals across this area over a 10-year period (2006–2015) using a questionnaire about sex, age, primary site, clinical symptoms, pathology, Union for International Cancer Control (UICC) staging, serological exam, treatment, and survival. A total of 620 NPC patients were identified. The age-standardized incidence of NPC from 2006 to 2015 was 0.27 per 100,000 individuals per year. There were no significant differences between this study and the previous two studies conducted in the same area of Japan. The five-year overall survival rate for all patients was 75.9%, while those for patients with stages I, II, III, and IVA were 97%, 91%, 79%, and 68%, respectively. The age-standardized annual incidence of NPC in the present study was 0.27 per 100,000 individuals per year, which was relatively low and stable. The five-year overall survival rate for all NPC patients was significantly improved in this decade compared with previous studies. The smoking rates in male and female NPC patients were 64.5% and 18.8%, respectively, thereby suggesting the involvement of smoking in the incidence of NPC. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Amplification of the EGFR and CCND1 Are Coordinated and Play Important Roles in the Progression of Oral Squamous Cell Carcinomas
Cancers 2019, 11(6), 760; https://doi.org/10.3390/cancers11060760 - 31 May 2019
Cited by 4
Abstract
Oral squamous cell carcinoma (OSCC) is a common cancer in Taiwan and worldwide. To provide some clues for clinical management of OSCC, 72 advanced-stage OSCCs were analyzed using two microarray platforms (26 cases with Affymetrix 500 K and 46 cases with Affymetrix SNP [...] Read more.
Oral squamous cell carcinoma (OSCC) is a common cancer in Taiwan and worldwide. To provide some clues for clinical management of OSCC, 72 advanced-stage OSCCs were analyzed using two microarray platforms (26 cases with Affymetrix 500 K and 46 cases with Affymetrix SNP 6.0). Genomic identification of significant targets in cancer analyses were used to identify significant copy number alterations (CNAs) using a q-value cutoff of 0.25. Among the several significant regions, 12 CNAs were common between these two platforms. Two gain regions contained the well-known oncogenes EGFR (7p11.2) and CCND1 (11q13.3) and several known cancer suppressor genes, such as FHIT (3p14.2–p12.1), FAT1 (4q35.1), CDKN2A (9p21.3), and ATM (11q22.3–q24.3), reside within the 10 deletion regions. Copy number gains of EGFR and CCND1 were further confirmed by fluorescence in situ hybridization and TaqMan CN assay, respectively, in 257 OSCC cases. Our results indicate that EGFR and CCND1 CNAs are significantly associated with clinical stage, tumor differentiation, and lymph node metastasis. Furthermore, EGFR and CCND1 CNAs have an additive effect on OSCC tumor progression. Thus, current genome-wide CNA analysis provides clues for future characterization of important oncogenes and tumor suppressor genes associated with the behaviors of the disease. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Polymorphisms of Mismatch Repair Pathway Genes Predict Clinical Outcomes in Oral Squamous Cell Carcinoma Patients Receiving Adjuvant Concurrent Chemoradiotherapy
Cancers 2019, 11(5), 598; https://doi.org/10.3390/cancers11050598 - 29 Apr 2019
Cited by 2
Abstract
Background: We aimed to investigate the association between single-nucleotide polymorphisms (SNP) in mismatch repair (MMR) pathway genes and survival in patients with oral squamous cell carcinoma (OSCC) who received adjuvant concurrent chemoradiotherapy (CCRT). Methods: Using the Sequenom iPLEX MassARRAY system, five SNPs in [...] Read more.
Background: We aimed to investigate the association between single-nucleotide polymorphisms (SNP) in mismatch repair (MMR) pathway genes and survival in patients with oral squamous cell carcinoma (OSCC) who received adjuvant concurrent chemoradiotherapy (CCRT). Methods: Using the Sequenom iPLEX MassARRAY system, five SNPs in four major MMR genes were genotyped in 319 patients with OSCC who received CCRT treatment. Kaplan–Meier survival curves and Cox proportional hazard regression models were used to assess overall survival (OS) and disease-free survival (DFS) among MMR genotypes. Results: The results of Kaplan–Meier survival analysis revealed that the MutS homolog 2 (MSH2) rs3732183 polymorphism showed a borderline significant association with DFS (log-rank p = 0.089). Participants with the MSH2 rs3732183 GG genotype exhibited a relatively low risk of recurrence (hazard ratio (HR) = 0.45; 95% confidence interval (CI) = 0.22–0.96; p = 0.039). In addition, the MutL homolog 1 (MLH1) rs1800734 GG genotype carriers exhibited higher OS (HR = 0.52, 95% CI = 0.27–1.01; p = 0.054) and DFS (HR = 0.49, 95% CI = 0.26–0.92; p = 0.028) rates. Conclusions: Our results indicated that the GG genotypes of MSH2 rs3732183 and MLH1 rs1800734 are associated with relatively high survival in OSCC patients treated using adjuvant CCRT. These polymorphisms may serve as prognosis predictors in OSCC patients. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Genetic Variants as Predictive Markers for Ototoxicity and Nephrotoxicity in Patients with Locally Advanced Head and Neck Cancer Treated with Cisplatin-Containing Chemoradiotherapy (The PRONE Study)
Cancers 2019, 11(4), 551; https://doi.org/10.3390/cancers11040551 - 17 Apr 2019
Cited by 1
Abstract
Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate [...] Read more.
Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate genetic variants as predictors for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10 genetic variants and evaluated for their association with cisplatin-induced ototoxicity (ACYP2, COMT, TPMT and WFS1) and nephrotoxicity (OCT2, MATE and XPD). Ototoxicity was determined by patient-reported complaints as well as tone audiometrical assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance during treatment compared to baseline. A significant association was observed between carriership of the A allele for rs1872328 in the ACYP2 gene and cisplatin-induced clinically determined ototoxicity (p = 0.019), and not for ototoxicity measured by tone audiometrical assessments (p = 0.449). Carriership of a T allele for rs316019 in the OCT2 gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (p = 0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients genetic variants in ACYP2 are significantly associated with clinically determined ototoxicity. Validation studies are necessary to prove the added value for individualized treatments plans in these patients. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
The Prognostic Roles of Pretreatment Circulating Tumor Cells, Circulating Cancer Stem-Like Cells, and Programmed Cell Death-1 Expression on Peripheral Lymphocytes in Patients with Initially Unresectable, Recurrent or Metastatic Head and Neck Cancer: An Exploratory Study of Three Biomarkers in One-time Blood Drawing
Cancers 2019, 11(4), 540; https://doi.org/10.3390/cancers11040540 - 15 Apr 2019
Cited by 1
Abstract
Circulating tumor cells (CTCs) and immune status are strongly related to cancer prognosis, although few studies have examined both factors. This prospective observational study (ClinicalTrials.gov: NCT02420600) evaluated whether CTCs, circulating cancer stem-like cells (cCSCs), and peripheral lymphocytes with/without Programmed cell death protein 1 [...] Read more.
Circulating tumor cells (CTCs) and immune status are strongly related to cancer prognosis, although few studies have examined both factors. This prospective observational study (ClinicalTrials.gov: NCT02420600) evaluated whether CTCs, circulating cancer stem-like cells (cCSCs), and peripheral lymphocytes with/without Programmed cell death protein 1 (PD-1) expression were associated with prognosis among patients receiving palliative chemotherapy for initially unresectable, recurrent/metastatic head and neck squamous cell carcinoma (rmHNSCC). Thirty-four patients were enrolled between January 2015 and June 2016. Overall survival (OS) was associated with a higher CTC number (hazard ratio [HR]: 1.01, p = 0.0004) and cCSC ratio (HR: 29.903, p < 0.0001). Progression-free survival (PFS) was also associated with CTC number (HR: 1.013, p = 0.002) and cCSC ratio (HR: 10.92, p = 0.003). A CD8+ proportion of ≥ 17% was associated with improved OS (HR: 0.242, p = 0.004). A CD4: CD8 ratio of >1.2 was associated with poorer trend of PFS (HR: 2.12, p = 0.064). PD-1 expression was not associated with survival outcomes. Baseline CTCs, cCSC ratio, and CD8+ ratio may predict prognosis in rmHNSCC. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Genetic Susceptibility in Head and Neck Squamous Cell Carcinoma in a Spanish Population
Cancers 2019, 11(4), 493; https://doi.org/10.3390/cancers11040493 - 07 Apr 2019
Cited by 4
Abstract
Despite classical environmental risk factors like tobacco, alcohol or viral infection, not all individuals develop head and neck cancer. Therefore, identification of the genetic susceptibility produced by single nucleotide polymorphisms (SNPs) is an important task. A total of 296 human papillomavirus negative head [...] Read more.
Despite classical environmental risk factors like tobacco, alcohol or viral infection, not all individuals develop head and neck cancer. Therefore, identification of the genetic susceptibility produced by single nucleotide polymorphisms (SNPs) is an important task. A total of 296 human papillomavirus negative head and neck cancer (HNC) patients (126 laryngeal, 100 pharyngeal and 70 oral cavity) were included in the study, involving 29 candidate SNPs in genes within important carcinogenic pathways (oncogenesis and tumour suppression, DNA repair, inflammation, oxidation and apoptosis). Genotyping was performed using TaqMan probes or restriction fragment length assays in peripheral blood DNA. In addition, 259 paired controls were also evaluated with the same risk factors for each specific location. Nine SNPs in DNA repair (ERCC1 rs11615, ERCC2 rs13181), inflammatory (IL2 rs2069762, IL6 rs1800795), oxidative (NFE2L2 rs13035806 and rs2706110) and apoptotic genes (TP53 rs1042522, MDM2 rs2279744, BCL2 rs2279115) were differently associated with HNSCC susceptibility by location. Some of these SNPs were not described before in this tumour type. In conclusion, we describe several SNPs associated with HNC in a Spanish population. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
Open AccessFeature PaperArticle
Unlocking the Potential of Saliva-Based Test to Detect HPV-16-Driven Oropharyngeal Cancer
Cancers 2019, 11(4), 473; https://doi.org/10.3390/cancers11040473 - 03 Apr 2019
Cited by 5
Abstract
The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is rising in high-income countries, including Australia. Increasing evidence suggests that accurate HPV testing is pivotal for clinical decision making and treatment planning in these patients. Recently, the eighth edition of the American Joint [...] Read more.
The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is rising in high-income countries, including Australia. Increasing evidence suggests that accurate HPV testing is pivotal for clinical decision making and treatment planning in these patients. Recently, the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor–node–metastasis (TNM) staging system for OPC (based on the p16INK4a (p16) status) was proposed and has been implemented. However, the applicability of this new staging system is still far from clear. In our study, n = 127 OPC patients from Queensland, Australia were recruited, and the tumor p16 expression in these patients was examined using immunohistochemical (IHC) analysis. HPV-16 genotyping, viral load, and physical status (episomal versus integrated) in the saliva samples of OPC patients were determined using the qPCR method. A good inter-rater agreement (k = 0.612) was found between tumor p16 expression and oral HPV-16 infection in OPC. Importantly, according to the eighth edition staging system, HPV-16 DNA viral load (>10 copies/50 ng) was significantly associated with the advanced stages of OPC. In concordance with previous studies, a mixed HPV-16 form (partially or fully integrated) was predominately found in OPC patients. Taken together, our data support HPV-16 detection in saliva as a screening biomarker to identify people within the community who are at risk of developing OPC. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy
Cancers 2019, 11(4), 445; https://doi.org/10.3390/cancers11040445 - 29 Mar 2019
Cited by 4
Abstract
About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance [...] Read more.
About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Influence of Tea Consumption on the Development of Second Esophageal Neoplasm in Patients with Head and Neck Cancer
Cancers 2019, 11(3), 387; https://doi.org/10.3390/cancers11030387 - 19 Mar 2019
Cited by 1
Abstract
Alcohol is an important risk factor for the development of second esophageal squamous-cell carcinoma (ESCC) in head and neck squamous-cell carcinoma (HNSCC) patients. However, the influence of tea consumption is uncertain. We prospectively performed endoscopic screening in incident HNSCC patients to identify synchronous [...] Read more.
Alcohol is an important risk factor for the development of second esophageal squamous-cell carcinoma (ESCC) in head and neck squamous-cell carcinoma (HNSCC) patients. However, the influence of tea consumption is uncertain. We prospectively performed endoscopic screening in incident HNSCC patients to identify synchronous esophageal neoplasm. In total, 987 patients enrolled between October 2008 and December 2017 and were analyzed. In vitro studies were conducted to investigate the effect of epigallocatechin gallate (EGCG) on the betel alkaloid, arecoline-stimulated carcinogenesis in two ESCC cell lines. There were 151 patients (15.3%) diagnosed to have synchronous esophageal neoplasm, including 88 low-grade dysplasia, 30 high-grade dysplasia and 33 squamous-cell carcinoma (SCC). Tea consumption was associated with a significantly lower risk of having esophageal high-grade dysplasia or SCC in HNSCC patients, especially those who were betel nut chewers, alcohol drinkers or cigarette smokers (all adjusted odds ratio were 0.5; p-values: 0.045, 0.045 and 0.049 respectively). In vitro studies indicated that EGCG suppressed arecoline-induced ESCC cell proliferation and colony formation through the inhibition of the Akt and ERK1/2 pathway in a reactive oxygen species-independent manner. In conclusion, tea consumption may protect against the development of second esophageal neoplasms among HNSCC patients, especially those who regularly consume betel nuts, alcohol and cigarettes. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Clinical Management of Blood–Brain Barrier Disruptions after Active Raster-Scanned Carbon Ion Re-Radiotherapy in Patients with Recurrent Head-and-Neck Cancer
Cancers 2019, 11(3), 383; https://doi.org/10.3390/cancers11030383 - 19 Mar 2019
Cited by 3
Abstract
Purpose: The aim of the current evaluation was to assess central nervous system necrosis (CNSN) after re-irradiation with carbon ions (CR) in two-hundred seventeen (n = 217) patients with recurrent head-and-neck cancer (HNC). Methods: Thirty-six (n = 36) patients with CNSN [...] Read more.
Purpose: The aim of the current evaluation was to assess central nervous system necrosis (CNSN) after re-irradiation with carbon ions (CR) in two-hundred seventeen (n = 217) patients with recurrent head-and-neck cancer (HNC). Methods: Thirty-six (n = 36) patients with CNSN were assessed retrospectively regarding clinical symptoms and radiographic response. Results: CNSN were classified according to clinical management in line with the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. At a median follow-up of 25.3 months (range 3.3–79.9 months), the median time interval until occurrence of grade I, II, and III CNSN was 9.2 months (range 2.8–75.0 months), 10.2 months (range 2.3–60.5 months), and 16.6 months (range 8.7–32.5 months), respectively. In one patient with an adenocarcinoma infiltrating the frontal lobe, an extensive CNSN grade IV was suspected but the patient declined surgical intervention. Radiographic response after treatment of CNSN grade I, II, and III, defined as ≥25% reduction of the T2 alteration on Magnetic Resonance Imaging (MRI), was observed in 4 (16.0%), 5 (29.4%), and 4 (80%) patients, respectively. Conclusion: CNSN occurred late and frequent after re-irradiation with carbon ions in patients with HNC infiltrating the base of skull. The clinical outcome with adequate treatment was encouraging but correct diagnosis of CNSN remains challenging. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
The Novel Role of SOX2 as an Early Predictor of Cancer Risk in Patients with Laryngeal Precancerous Lesions
Cancers 2019, 11(3), 286; https://doi.org/10.3390/cancers11030286 - 01 Mar 2019
Cited by 5
Abstract
The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. [...] Read more.
The SOX2 gene located at 3q26 is frequently amplified and overexpressed in multiple cancers, including head and neck squamous cell carcinomas (HNSCC). The tumor-promoting activity and involvement of SOX2 in tumor progression has been extensively demonstrated, thereby emerging as a promising therapeutic target. However, the role of SOX2 in early stages of tumorigenesis and its possible contribution to malignant transformation remain unexplored. This study investigates for the first time SOX2 protein expression by immunohistochemistry and gene amplification by real-time PCR using a large series of 94 laryngeal precancerous lesions. Correlations with the histopathological classification and the risk of progression to invasive carcinoma were established. Nuclear SOX2 expression was frequently detected in 38 (40%) laryngeal dysplasias, whereas stromal cells and normal adjacent epithelia showed negative expression. SOX2 gene amplification was detected in 18 (33%) of 55 laryngeal dysplasias. Univariate Cox analysis showed that SOX2 gene amplification (p = 0.046) and protein expression (p < 0.001) but not histological grading (p = 0.432) were significantly associated with laryngeal cancer risk. In multivariate stepwise analysis including age, tobacco, histology, SOX2 gene amplification and SOX2 expression, SOX2 expression (HR = 3.531, 95% CI 1.144 to 10.904; p = 0.028) was the only significant independent predictor of laryngeal cancer development. These findings underscore the relevant role of SOX2 in early tumorigenesis and a novel clinical application of SOX2 expression as independent predictor of laryngeal cancer risk in patients with precancerous lesions beyond current WHO histological grading. Therefore, targeting SOX2 could lead to effective strategies for both cancer prevention and treatment. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
Cancers 2018, 10(12), 476; https://doi.org/10.3390/cancers10120476 - 30 Nov 2018
Cited by 3
Abstract
Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to [...] Read more.
Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms. Our lab has previously identified that the anti-cancer activity of propranolol, a non-selective beta-blocker, is associated with inhibition of mitochondrial metabolism in head and neck squamous cell carcinoma (HNSCC). In response to propranolol, however, HNSCC exhibits heightened glycolytic activity, which may limit the effectiveness of propranolol as a single agent. Thus, we hypothesized that propranolol’s metabolic effects promote a state of enhanced glucose dependence, and that propranolol together with glycolytic inhibition would provide a highly effective therapeutic combination in HNSCC. Here, we show that glucose deprivation synergizes with propranolol for anti-cancer activity, and that the rational combination of propranolol and dichloroacetate (DCA), a clinically available glycolytic inhibitor, dramatically attenuates tumor cell metabolism and mTOR signaling, inhibits proliferation and colony formation, and induces apoptosis. This therapeutic combination displays efficacy in both human papillomavirus-positive (HPV(+)) and HPV(−) HNSCC cell lines, as well as a recurrent/metastatic model, while leaving normal tonsil epithelial cells relatively unaffected. Importantly, the combination significantly delays tumor growth in vivo with no evidence of toxicity. Additionally, the combination of propranolol and DCA enhances the effects of chemoradiation and sensitizes resistant cells to cisplatin and radiation. This novel therapeutic combination represents a promising treatment strategy which may overcome some of the limitations of targeting individual metabolic pathways in cancer. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Prognostic Markers in Head and Neck Cancer Patients Treated with Nivolumab
Cancers 2018, 10(12), 466; https://doi.org/10.3390/cancers10120466 - 23 Nov 2018
Cited by 3
Abstract
To investigate whether peripheral blood biomarkers predict the outcome of anti-PD-1 antibody treatment for head and neck squamous cell carcinoma (HNSCC). Patients treated with nivolumab for platinum-refractory recurrent or metastatic HNSCC were retrospectively reviewed. Fifty-three patients treated between April 2017 and March 2018 [...] Read more.
To investigate whether peripheral blood biomarkers predict the outcome of anti-PD-1 antibody treatment for head and neck squamous cell carcinoma (HNSCC). Patients treated with nivolumab for platinum-refractory recurrent or metastatic HNSCC were retrospectively reviewed. Fifty-three patients treated between April 2017 and March 2018 were included in the study. The median progression-free survival (PFS) and overall survival (OS) were 2.5 and 8.7 months, respectively. In the univariate analysis, performance status (PS) ≥ 3, relative neutrophil count ≥ 0.65, relative lymphocyte count ≥ 0.17, and relative eosinophil count (REC) ≥ 0.015 were significantly associated with both PFS and OS. On multivariate analysis, PS ≥ 3 and REC ≥ 0.015 were significantly associated with PFS and OS. Low REC and poor PS were independent poor prognostic factors for both PFS and OS in patients with recurrent or metastatic HNSCC treated with nivolumab. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessArticle
Factors Secreted by Cancer-Associated Fibroblasts that Sustain Cancer Stem Properties in Head and Neck Squamous Carcinoma Cells as Potential Therapeutic Targets
Cancers 2018, 10(9), 334; https://doi.org/10.3390/cancers10090334 - 17 Sep 2018
Cited by 14
Abstract
This study investigates for the first time the crosstalk between stromal fibroblasts and cancer stem cell (CSC) biology in head and neck squamous cell carcinomas (HNSCC), with the ultimate goal of identifying effective therapeutic targets. The effects of conditioned media from cancer-associated fibroblasts [...] Read more.
This study investigates for the first time the crosstalk between stromal fibroblasts and cancer stem cell (CSC) biology in head and neck squamous cell carcinomas (HNSCC), with the ultimate goal of identifying effective therapeutic targets. The effects of conditioned media from cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs) on the CSC phenotype were assessed by combining functional and expression analyses in HNSCC-derived cell lines. Further characterization of CAFs and NFs secretomes by mass spectrometry was followed by pharmacologic target inhibition. We demonstrate that factors secreted by CAFs but not NFs, in the absence of serum/supplements, robustly increased anchorage-independent growth, tumorsphere formation, and CSC-marker expression. Modulators of epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR), and platelet-derived growth factor receptor (PDGFR) activity were identified as paracrine cytokines/factors differentially secreted between CAFs and NFs, in a mass spectrometry analysis. Furthermore, pharmacologic inhibition of EGFR, IGFR, and PDGFR significantly reduced CAF-induced tumorsphere formation and anchorage-independent growth suggesting a role of these receptor tyrosine kinases in sustaining the CSC phenotype. These findings provide novel insights into tumor stroma–CSC communication, and potential therapeutic targets to effectively block the CAF-enhanced CSC niche signaling circuit. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Review

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Open AccessReview
Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications
Cancers 2019, 11(5), 616; https://doi.org/10.3390/cancers11050616 - 02 May 2019
Cited by 8
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. Despite advances in the treatment management, locally advanced disease has a poor prognosis, with a 5-year survival rate of approximately 50%. The growth of HNSCC is maintained by [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. Despite advances in the treatment management, locally advanced disease has a poor prognosis, with a 5-year survival rate of approximately 50%. The growth of HNSCC is maintained by a population of cancer stem cells (CSCs) which possess unlimited self-renewal potential and induce tumor regrowth if not completely eliminated by therapy. The population of CSCs is not only a promising target for tumor treatment, but also an important biomarker to identify the patients at risk for therapeutic failure and disease progression. This review aims to provide an overview of the recent pre-clinical and clinical studies on the biology and potential therapeutic implications of HNSCC stem cells. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessReview
Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go?
Cancers 2019, 11(4), 472; https://doi.org/10.3390/cancers11040472 - 03 Apr 2019
Cited by 6
Abstract
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice [...] Read more.
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessReview
The Head and Neck Squamous Cell Carcinoma Microenvironment as a Potential Target for Cancer Therapy
Cancers 2019, 11(4), 440; https://doi.org/10.3390/cancers11040440 - 28 Mar 2019
Cited by 7
Abstract
Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence [...] Read more.
Similarly to other types of malignant tumours, the incidence of head and neck cancer is increasing globally. It is frequently associated with smoking and alcohol abuse, and in a broader sense also with prolonged exposure to these factors during ageing. A higher incidence of tumours observed in younger populations without a history of alcohol and tobacco abuse may be due to HPV infection. Malignant tumours form an intricate ecosystem of cancer cells, fibroblasts, blood/lymphatic capillaries and infiltrating immune cells. This dynamic system, the tumour microenvironment, has a significant impact on the biological properties of cancer cells. The microenvironment participates in the control of local aggressiveness of cancer cells, their growth, and their consequent migration to lymph nodes and distant organs during metastatic spread. In cancers originating from squamous epithelium, a similarity was demonstrated between the cancer microenvironment and healing wounds. In this review, we focus on the specificity of the microenvironment of head and neck cancer with emphasis on the mechanism of intercellular crosstalk manipulation for potential therapeutic application. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessReview
Circulating Tumour Cells (CTC), Head and Neck Cancer and Radiotherapy; Future Perspectives
Cancers 2019, 11(3), 367; https://doi.org/10.3390/cancers11030367 - 15 Mar 2019
Cited by 3
Abstract
Head and neck cancer is the seventh most common cancer in Australia and globally. Despite the current improved treatment modalities, there is still up to 50–60% local regional recurrence and or distant metastasis. High-resolution medical imaging technologies such as PET/CT and MRI do [...] Read more.
Head and neck cancer is the seventh most common cancer in Australia and globally. Despite the current improved treatment modalities, there is still up to 50–60% local regional recurrence and or distant metastasis. High-resolution medical imaging technologies such as PET/CT and MRI do not currently detect the early spread of tumour cells, thus limiting the potential for effective minimal residual detection and early diagnosis. Circulating tumour cells (CTCs) are a rare subset of cells that escape from the primary tumour and enter into the bloodstream to form metastatic deposits or even re-establish themselves in the primary site of the cancer. These cells are more aggressive and accumulate gene alterations by somatic mutations that are the same or even greater than the primary tumour because of additional features acquired in the circulation. The potential application of CTC in clinical use is to acquire a liquid biopsy, by taking a reliable minimally invasive venous blood sample, for cell genotyping during radiotherapy treatment to monitor the decline in CTC detectability, and mutational changes in response to radiation resistance and radiation sensitivity. Currently, very little has been published on radiation therapy, CTC, and circulating cancer stem cells (CCSCs). The prognostic value of CTC in cancer management and personalised medicine for head and neck cancer radiotherapy patients requires a deeper understanding at the cellular level, along with other advanced technologies. With this goal, this review summarises the current research of head and neck cancer CTC, CCSC and the molecular targets for personalised radiotherapy response. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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Open AccessReview
Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Question of Belief
Cancers 2019, 11(1), 15; https://doi.org/10.3390/cancers11010015 - 22 Dec 2018
Cited by 4
Abstract
Induction chemotherapy (IC) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) has been used for decades. However, its role is yet to be clearly defined outside of larynx preservation. Patients with high risk of distant failure might potentially benefit from [...] Read more.
Induction chemotherapy (IC) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) has been used for decades. However, its role is yet to be clearly defined outside of larynx preservation. Patients with high risk of distant failure might potentially benefit from sequential treatment. It is now widely accepted that TPF (docetaxel, cisplatin, and fluorouracil) is the standard IC regimen. Essays that have compared this approach with the standard of care, concurrent chemoradiotherapy (CCRT), are mostly inconclusive. Radiotherapy (RT) can be used in the post-IC setting and be sensitized by chemotherapy or cetuximab. Again, no consensus exists but there seems to be trend in favor of potentiation by cisplatin. Less toxic schemes of IC are tested as toxicity is a major issue with TPF. IC might have an interesting role in human papilloma virus (HPV)-related LA HNSCC and lead to CCRT de-escalation. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
Open AccessReview
Role of COX-2/PGE2 Mediated Inflammation in Oral Squamous Cell Carcinoma
Cancers 2018, 10(10), 348; https://doi.org/10.3390/cancers10100348 - 22 Sep 2018
Cited by 11
Abstract
A significant amount of research indicates that the cyclooxygenase/prostaglandin E2 (PGE2) pathway of inflammation contributes to the development and progression of a variety of cancers, including squamous cell carcinoma of the oral cavity and oropharynx (OSCC). Although there have been promising results from [...] Read more.
A significant amount of research indicates that the cyclooxygenase/prostaglandin E2 (PGE2) pathway of inflammation contributes to the development and progression of a variety of cancers, including squamous cell carcinoma of the oral cavity and oropharynx (OSCC). Although there have been promising results from studies examining the utility of anti-inflammatory drugs in the treatment of OSCC, this strategy has been met with only variable success and these drugs are also associated with toxicities that make them inappropriate for some OSCC patients. Improved inflammation-targeting therapies require continued study of the mechanisms linking inflammation and progression of OSCC. In this review, a synopsis of OSCC biology will be provided, and recent insights into inflammation related mechanisms of OSCC pathobiology will be discussed. The roles of prostaglandin E2 and cluster of differentiation factor 147 (CD147) will be presented, and evidence for their interactions in OSCC will be explored. Through continued investigation into the protumourigenic pathways of OSCC, more treatment modalities targeting inflammation-related pathways can be designed with the hope of slowing tumour progression and improving patient prognosis in patients with this aggressive form of cancer. Full article
(This article belongs to the Special Issue Targeting Head and Neck Cancer)
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