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Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

ABSTRACT: Despite improvements in functional outcomes attributable to advances in radiotherapy, chemotherapy, surgical techniques, and imaging techniques, survival in head and neck squamous cell carcinoma (HNSCC) patients has improved only marginally during the last couple of decades, and optimal therapy has yet to be devised. Genomic complexity and intratumoral genetic heterogeneity may contribute to treatment resistance and the propensity for locoregional recurrence. Countering this, it demands a significant effort from both basic and clinical scientists in the search for more effective targeted therapies. Recent genomewide studies have provided valuable insights into the genetic basis of HNSCC, uncovering potential new therapeutic opportunities. In addition, several studies have elucidated how inflammatory, immune, and stromal cells contribute to the particular properties of these neoplasms. In the present review, we introduce recent findings on genomic aberrations resulting from whole-genome sequencing of HNSCC, we discuss how the particular microenvironment affects the pathogenesis of this disease, and we describe clinical trials exploring new perspectives on the use of combined genetic and cellular targeted therapies.

SUBMITTER: Ausoni S

PROVIDER: S-EPMC5524458 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

Ausoni Simonetta S Boscolo-Rizzo Paolo P Singh Bhuvanesh B Da Mosto Maria Cristina MC Spinato Giacomo G Tirelli Giancarlo G Spinato Roberto R Azzarello Giuseppe G

Cancer metastasis reviews 20160901 3

Despite improvements in functional outcomes attributable to advances in radiotherapy, chemotherapy, surgical techniques, and imaging techniques, survival in head and neck squamous cell carcinoma (HNSCC) patients has improved only marginally during the last couple of decades, and optimal therapy has yet to be devised. Genomic complexity and intratumoral genetic heterogeneity may contribute to treatment resistance and the propensity for locoregional recurrence. Countering this, it demands a signif ...[more]

PMID: 27194534

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Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

Project description:Treatment of locoregionally advanced head and neck squamous cell carcinoma involves a multidisciplinary approach that combines surgery, radiotherapy, and systemic therapy. These curative strategies are associated with significant acute and long-term toxicities. With the emergence of human papillomavirus (HPV) as an etiologic factor associated primarily with oropharyngeal squamous cell carcinoma, higher cure rates juxtaposed with substantial treatment-related morbidity and mortality has led to interest in de-escalated therapeutic strategies, with the goal of optimizing oncologic outcomes while reducing treatment-related toxicity. Currently explored strategies include replacing, reducing, or omitting cytotoxic chemotherapy; reducing dose or volume of radiotherapy; and incorporation of less-invasive surgical approaches. Potential biomarkers to select patients for treatment de-escalation include clinical risk stratification, adjuvant de-escalation based on pathologic features, response to induction therapy, and molecular markers. The optimal patient selection and de-escalation strategy is critically important in the evolving treatment of locoregional head and neck cancer. Recently, two large phase III trials, RTOG 1016 and De-ESCALaTE, failed to de-escalate treatment in HPV-associated head and neck cancer by demonstrating inferior outcomes by replacing cisplatin with cetuximab in combination with radiation. This serves as a cautionary tale in the future design of de-escalation trials in this patient population, which will need to leverage toxicity and efficacy endpoints. Our review summarizes completed and ongoing de-escalation trials in head and neck cancer, with particular emphasis on biomarkers for patient selection and clinical trial design. IMPLICATIONS FOR PRACTICE: The toxicity associated with standard multimodality treatment for head and neck cancer underscores the need to seek less-intensive therapies with a reduced long-term symptom burden through de-escalated treatment paradigms that minimize toxicity while maintaining oncologic control in appropriately selected patients. Controversy regarding the optimal de-escalation strategy and criteria for patient selection for de-escalated therapy has led to multiple parallel strategies undergoing clinical investigation. Well-designed trials that optimize multimodal strategies are needed. Given the absence of positive randomized trials testing de-escalated therapy to date, practicing oncologists should exercise caution and administer established standard-of-care therapy outside the context of a clinical trial.

Dataset Information

Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

Publications

Targeting cellular and molecular drivers of head and neck squamous cell carcinoma: current options and emerging perspectives.

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