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Prognostic and therapeutic potential of nuclear receptors in head and neck squamous cell carcinomas.

ABSTRACT: Head and neck squamous cell carcinomas are among the most common neoplasms worldwide and characterized by local tumor aggressiveness, high rate of early recurrences, development of metastasis, and second primary cancers. Despite modern therapeutic strategies and sophisticated surgical management, overall survival-rates remained largely unchanged over the last decades. Thus, the need for novel treatment options for this tumor entity is undeniable. A key event in carcinogenesis is the uncontrolled modulation of genetic programs. Nuclear receptors belong to a large superfamily of transcription factors implicated in a broad spectrum of physiological and pathophysiological processes, including cancer. Several nuclear receptors have also been associated with head and neck cancer. This review will summarize their mode of action, prognostic/therapeutic relevance, as well as preclinical and clinical studies currently targeting nuclear receptors in this tumor entity.

SUBMITTER: Knauer SK

PROVIDER: S-EPMC2753797 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Prognostic and therapeutic potential of nuclear receptors in head and neck squamous cell carcinomas.

Knauer Shirley K SK

Journal of oncology 20090924

Head and neck squamous cell carcinomas are among the most common neoplasms worldwide and characterized by local tumor aggressiveness, high rate of early recurrences, development of metastasis, and second primary cancers. Despite modern therapeutic strategies and sophisticated surgical management, overall survival-rates remained largely unchanged over the last decades. Thus, the need for novel treatment options for this tumor entity is undeniable. A key event in carcinogenesis is the uncontrolled ...[more]

PMID: 19794826

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Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC).

Project description:BACKGROUND: In order to improve therapy for HNSCC patients, novel methods to predict and combat local and/or distant tumour relapses are urgently needed. This study has been dedicated to the hypothesis that Rac1, a Rho GTPase, is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development. METHODS: Parental and radiation-resistant (IRR) HNSCC cells were used to support this hypothesis. All cells were investigated for their sensitivity to ionising radiation and cisplatin, Rac1 activity, its intracellular expression and subcellular localisation. Additionally, tumour tissues obtained from 60 HNSCC patients showing different therapy response were evaluated for intratumoral Rac1 expression. RESULTS: Radiation-resistant IRR cells also revealed resistance to cisplatin accompanied by increased expression, activity and trend towards nuclear translocation of Rac1 protein. Chemical inhibition of Rac1 expression and activity resulted in significant improvement of HNSCC sensitivity to ionising radiation and cisplatin. Preclinical results were confirmed in clinical samples. Although Rac1 was poorly presented in normal mucosa, tumour tissues revealed increased Rac1 expression. The most pronounced Rac1 presence was observed in HNSCC patients with poor early or late responses to chemo-radiotherapy. Tissues taken at recurrence were characterised not only by enhanced Rac1 expression but also increased nuclear Rac1 content. CONCLUSIONS: Increased expression, activity and subcellular localisation of Rac1 could be associated with lower early response rate and higher risk of tumour recurrences in HNSCC patients and warrants further validation in larger independent studies. Inhibition of Rac1 activity can be useful in overcoming treatment resistance and could be proposed for HNSCC patients with primary or secondary chemo-radioresistance.

| S-EPMC4037830 | biostudies-other

Therapeutic insights from genomic studies of head and neck squamous cell carcinomas.

Project description:Large and comprehensive genomic surveys of head and neck squamous cell carcinomas (HNSCC) are now greatly increasing our understanding of the diversity of this disease and the key genomic changes that drive these tumors. The results from these studies are beginning to inform the introduction of novel therapies for patients with HNSCCs. Here, we review some of the key findings from recent genomic studies of head and neck cancers, including the most comprehensive study to date from The Cancer Genome Atlas Network.

| S-EPMC4355279 | biostudies-literature

A Transcriptomic Analysis of Head and Neck Squamous Cell Carcinomas for Prognostic Indications.

Project description:Survival analysis of the Cancer Genome Atlas (TCGA) dataset is a well-known method for discovering gene expression-based prognostic biomarkers of head and neck squamous cell carcinoma (HNSCC). A cutoff point is usually used in survival analysis for patient dichotomization when using continuous gene expression values. There is some optimization software for cutoff determination. However, the software's predetermined cutoffs are usually set at the medians or quantiles of gene expression values. There are also few clinicopathological features available in pre-processed datasets. We applied an in-house workflow, including data retrieving and pre-processing, feature selection, sliding-window cutoff selection, Kaplan-Meier survival analysis, and Cox proportional hazard modeling for biomarker discovery. In our approach for the TCGA HNSCC cohort, we scanned human protein-coding genes to find optimal cutoff values. After adjustments with confounders, clinical tumor stage and surgical margin involvement were found to be independent risk factors for prognosis. According to the results tables that show hazard ratios with Bonferroni-adjusted p values under the optimal cutoff, three biomarker candidates, CAMK2N1, CALML5, and FCGBP, are significantly associated with overall survival. We validated this discovery by using the another independent HNSCC dataset (GSE65858). Thus, we suggest that transcriptomic analysis could help with biomarker discovery. Moreover, the robustness of the biomarkers we identified should be ensured through several additional tests with independent datasets.

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Squamous cell carcinomas of the head and neck.

Project description: Not available

| S-EPMC1124330 | biostudies-literature

Identification of new candidate therapeutic target genes in head and neck squamous cell carcinomas.

Project description:BackgroundWe aimed at identifying druggable molecular alterations at the RNA level from untreated HNSCC patients, and assessing their prognostic significance.MethodsWe retrieved 96 HNSCC patients who underwent primary surgery. Real-time quantitative RT-PCR was used to analyze a panel of 42 genes coding for major druggable proteins. Univariate and multivariate analyses were performed to assess the prognostic significance of overexpressed genes.ResultsMedian age was 56 years [35-78]. Most of patients were men (80%) with a history of alcohol (70.4%) and/or tobacco consumption (72.5%). Twelve patients (12%) were HPV-positive. Most significantly overexpressed genes involved cell cycle regulation (CCND1 [27%], CDK6 [21%]), tyrosine kinase receptors (MET [18%], EGFR [14%]), angiogenesis (PGF [301%], VEGFA [14%]), and immune system (PDL1/CD274 [28%]). PIK3CA expression was an independent prognostic marker, associated with shorter disease-free survival.ConclusionsWe identified druggable overexpressed genes associated with a poor outcome that might be of interest for personalizing treatment of HNSCC patients.

| S-EPMC5216951 | biostudies-literature

Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas.

Project description:PurposeWe examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.Methods and materialsFGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models.ResultsFGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX.ConclusionsThese findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

| S-EPMC7321889 | biostudies-literature

Head and neck squamous cell carcinomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2009-03-12 | GSE12020 | GEO

ARG1 mRNA Level Is a Promising Prognostic Marker in Head and Neck Squamous Cell Carcinomas.

Project description:Head and neck squamous cell carcinomas (HNSCC) can be induced by smoking or alcohol consumption, but a growing part of cases relate to a persistent high-risk papillomavirus (HPV) infection. Viral etiology has a beneficial impact on the prognosis, which may be explained by a specific immune response. Tumor associated macrophages (TAMs) represent the main immune population of the tumor microenvironment with a controversial influence on the prognosis. In this study, the level, phenotype, and spatial distribution of TAMs were evaluated, and the expression of TAM-associated markers was compared in HPV positive (HPV+) and HPV negative (HPV-) tumors. Seventy-three formalin and embedded in paraffin (FFPE) tumor specimens were examined using multispectral immunohistochemistry for the detection of TAM subpopulations in the tumor parenchyma and stroma. Moreover, the mRNA expression of TAM markers was evaluated using RT-qPCR. Results were compared with respect to tumor etiology, and the prognostic significance was evaluated. In HPV- tumors, we observed more pro-tumorigenic M2 in the stroma and a non-macrophage arginase 1 (ARG1)-expressing population in both compartments. Moreover, higher mRNA expression of M2 markers-cluster of differentiation 163 (CD163), ARG1, and prostaglandin-endoperoxide synthase 2 (PTGS2)-was detected in HPV- patients, and of M1 marker nitric oxide synthase 2 (NOS2) in HPV+ group. The expression of ARG1 mRNA was revealed as a negative prognostic factor for overall survival of HNSCC patients.

| S-EPMC8065482 | biostudies-literature

Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities.

Project description:Spontaneously occurring canine oral squamous cell carcinomas (COSCC) are viewed as a useful model for human head and neck squamous cell carcinomas (HNSCC). To date however, the molecular basis of COSCC remains poorly understood. To identify changes pertinent to cancer cells in COSCC, we specifically analyzed tumor cells and matched normal epithelium from clinical formalin-fixed paraffin-embedded specimens using laser-capture-microdissection coupled with RNA-sequencing (RNAseq). Our results identify strong contributions of epithelial-to-mesenchymal transition (EMT), classical tumor-promoting (such as E2F, KRAS, MYC, mTORC1, and TGFB1 signaling) and immune-related pathways in the tumor epithelium of COSCC. Comparative analyses of COSCC with 43 paired tumor/normal HNSCC from The Cancer Genome Atlas revealed a high homology in transcriptional reprogramming, and identified processes associated with cell cycle progression, immune processes, and loss of cellular differentiation as likely central drivers of the disease. Similar to HNSCC, our analyses suggested a ZEB2-driven partial EMT in COSCC and identified selective upregulation of KRT14 and KRT17 in COSCC. Beyond homology in transcriptional signatures, we also found therapeutic vulnerabilities strongly conserved between the species: these included increased expression of PD-L1 and CTLA-4, coinciding with EMT and revealing the potential for immune checkpoint therapies, and overexpression of CDK4/6 that sensitized COSCC to treatment with palbociclib. In summary, our data significantly extend the current knowledge of molecular aberrations in COSCC and underline the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside.

| S-EPMC7642746 | biostudies-literature

Head and neck squamous cell carcinomas

Project description:This SuperSeries is composed of the following subset Series: GSE11929: Identification of a subgroup of head and neck cancers lacking numerical chromosomal aberrations GSE11931: Copy Number Alterations in HNSCC with or without Oncogene Expressing Human Papillomavirus Refer to individual Series

2009-03-11 | E-GEOD-12020 | biostudies-arrayexpress

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