Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors.
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ABSTRACT:
SUBMITTER: Fasano M
PROVIDER: S-EPMC8391435 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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Project description:Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an entity with peculiar clinical and molecular characteristics, which mainly arises from the reticulated epithelium lining the crypts of the palatine tonsils and the base of the tongue. The only head and neck site with a definite etiological association between persistent high-risk (HR) HPV infection and development of SCC is the oropharynx. HPV-positive malignancies represent 5-20% of all HNSCCs and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. HPV-16 is by far the most common HR HPV genotype detected in oropharyngeal SCC (OPSCC), and the only definitely carcinogenic genotype for the head and neck region. Patients with HPV-induced OPSCC are more likely to be middle-aged white men, non-smokers, non-drinkers or mild to moderate drinkers, with higher socioeconomic status and better performance status than subjects with HPV-unrelated SCC. HPV-induced HNSCCs are often described as non-keratinizing, poorly differentiated or basaloid carcinomas, and are diagnosed in earlier T-category with a trend for a more advanced N-category, with cystic degeneration, than the HPV-unrelated carcinomas. HPV positivity is associated with better response to treatment and modality-independent survival benefit. Treatment selection in HPV-related oropharyngeal carcinoma is becoming a critical issue, and although there is no evidence from randomized, controlled trials to support a treatment de-escalation in HPV-positive SCC, some investigators argue that intensive combined modality strategies may represent an overtreatment.
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Project description:Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.
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Project description:A minority of patients with metastatic head and neck squamous cell carcinoma (HNSCC) present with oligometastatic disease. Oligometastasis not only reflects a disease state, but might also present an opportunity for cure in the metastatic setting. Radical ablation of all oligometastatic sites may confer prolonged survival and possibly achieve cure in some patients. However, substantial debate remains about whether patients with oligometastatic disease could benefit from curative intent therapy or whether aggressive treatments expose some patients to futile toxicity. Optimal selection of patients, carefully balancing the currently known prognostic factors against the risks of toxicity is critical. Emerging evidence suggests that patients with a limited burden of disease, viral-related pharyngeal cancer, metachronous metastasis and lung-only metastasis may benefit most from this approach. Efforts are underway to identify biomarkers that can detect oligometastasis and better select patients who would derive the maximum benefit from an aggressive radical approach. The combination of radiotherapy and immunotherapy promises to enhance the anti-tumoral immune response and help overcome resistance. However, optimization of management algorithms, including patient selection, radiation dose and sequencing, will be critical in upcoming clinical trials. This review summarizes recent knowledge about the characteristics and investigational efforts regarding oligometastasis in HNSCC.
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Project description:The introduction of transoral endoscopic surgery has initiated a fundamental change in the treatment of head and neck cancer. The endoscopic approach minimizes the intraoperative trauma. Due to the lower burden for the patient and the savings potential these methods have gained wide acceptance. These transoral accesses routes allow experienced surgeons to reduce the morbidity of surgical resection with no deterioration of oncologic results. This suggests a further extension of the indication spectrum and a high growth potential for these techniques and equipment in the coming years. For selected patients with selected tumors the minimally invasive transoral surgery offers improved oncological and functional results. In the present paper, different surgical access routes are presented and their indications discussed.
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Project description:YRNAs are a class of non-coding RNAs that are components of the Ro60 ribonucleoprotein particle and are essential for initiation of DNA replication. Ro60 ribonucleoprotein particle is a target of autoimmune antibodies in patients suffering from systemic lupus erythematosus and Sjögren's syndrome. Deregulation of YRNAs has been confirmed in many cancer types, but not in head and neck squamous cell carcinoma (HNSCC). The main aim of this study was to determine the biological role of YRNAs in HNSCC, the expression of YRNAs, and their usefulness as potential HNSCC biomarkers. Using quantitative reverse transcriptase (qRT)-PCR, the expression of YRNAs was measured in HNSCC cell lines, 20 matched cancer tissues, and 70 FFPETs (Formaline-Fixed Paraffin-Embedded Tissue) from HNSCC patients. Using TCGA (The Cancer Genome Atlas) data, an analysis of the expression levels of selected genes, and clinical-pathological parameters was performed. The expression of low and high YRNA1 expressed groups were analysed using gene set enrichment analysis (GSEA). YRNA1 and YRNA5 are significantly downregulated in HNSCC cell lines. YRNA1 was found to be significantly downregulated in patients' tumour sample. YRNAs were significantly upregulated in T4 stage. YRNA1 showed the highest sensitivity, allowing to distinguish healthy from cancer tissue. An analysis of TCGA data revealed that expression of YRNA1 was significantly altered in the human papilloma virus (HPV) infection status. Patients with medium or high expression of YRNA1 showed better survival outcomes. It was noted that genes correlated with YRNA1 were associated with various processes occurring during cancerogenesis. The GSEA analysis showed high expression enrichment in eight vital processes for cancer development. YRNA1 influence patients' survival and could be used as an HNSCC biomarker. YRNA1 seems to be a good potential biomarker for HNSCC, however, more studies must be performed and these observations should be verified using an in vitro model.
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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.
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Project description:Signal transducer and activator of transcription-3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis, tumor progression, and drug resistance in head and neck squamous cell carcinoma (HNSCC). A decoy oligonucleotide targeting STAT3 offers a promising anti-tumor strategy, but achieving targeted tumor delivery of the decoy with systemic administration poses a significant challenge. We previously showed the potential for STAT3 decoy-loaded microbubbles, in conjunction with ultrasound targeted microbubble cavitation (UTMC), to decrease tumor growth in murine squamous cell carcinoma. As a next step towards clinical translation, we sought to determine the anti-tumor efficacy of our STAT3 decoy delivery platform against human HNSCC and the effect of higher STAT3 decoy microbubble loading on tumor cell inhibition. STAT3 decoy was loaded on cationic lipid microbubbles (STAT3-MB) or loaded on liposome-conjugated lipid microbubbles to form STAT3-loaded liposome-microbubble complexes (STAT3-LPX). UTMC treatment efficacy with these two formulations was evaluated in vitro using viability and apoptosis assays in CAL33 (human HNSCC) cells. Anti-cancer efficacy in vivo was performed in a CAL33 tumor murine xenograft model. UTMC with STAT3-MB caused significantly lower CAL33 cell viability compared to UTMC with STAT3-LPX (56.8±8.4% vs 84.5±8.8%, respectively, p<0.05). In vivo, UTMC with STAT3-MB had strong anti-tumor effects, with significantly less tumor burden and greater survival compared to that of UTMC with microbubbles loaded with a mutant control decoy and untreated control groups (p<0.05). UTMC with STAT3 decoy-loaded microbubbles significantly decreases human HNSSC tumor progression. These data set the stage for clinical translation of our microbubble platform as an imaged-guided, targeted delivery strategy for STAT3 decoy, or other nucleotide-based therapeutics, in human cancer treatment.
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