Targeted therapies for non-HPV-related head and neck cancer

challenges and opportunities in the context of predictive, preventive, and personalized medicine

Linah A. Shahoumi, William Andrew Yeudall

Research output: Contribution to journalReview article

Abstract

Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal lining of the upper aerodigestive tract, principally as a result of exposure to carcinogens present in tobacco products and alcohol, with oncogenic papillomaviruses also being recognized as etiological agents in a limited proportion of cases. As such, there is considerable scope for prevention of disease development and progression. However, despite multimodal approaches to treatment, tumor recurrence and metastatic disease are common problems, and clinical outcome is unsatisfactory. As our understanding of the genetics and biochemical aberrations in HNSCC has improved, so the development and use of molecularly targeted drugs to combat the disease have come to the fore. In this article, we review molecular mechanisms that alter signal transduction downstream of the epidermal growth factor receptor (EGFR) as well as those that perturb orderly cell cycle progression, such as p53 mutation, cyclin overexpression, and loss of cyclin-dependent kinase inhibitor function. We outline some of the tactics that have been employed to combat the altered biochemistry. These include blockade of the EGFR using humanized monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib and subsequent generations of TKIs, restoration of p53 function using MIRA compounds, and inhibition of cyclin-dependent kinase and aurora kinase activity using drugs such as palbociclib and alisertib. Knowledge of the underlying molecular mechanisms may be utilizable in order to predict disease behavior and tailor therapeutic interventions in a more personalized approach to improve clinical response. Use of liquid biopsy, omics platforms, and salivary diagnostics hold promise in this regard.

Original languageEnglish (US)
Pages (from-to)291-305
Number of pages15
JournalEPMA Journal
Volume10
Issue number3
DOIs
StatePublished - Sep 15 2019

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Precision Medicine
Preventive Medicine
Head and Neck Neoplasms
Medicine
Cyclin-Dependent Kinases
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Aurora Kinases
Antibodies, Monoclonal, Humanized
Cyclins
Tobacco Products
Pharmaceutical Preparations
Carcinogens
Biochemistry
Signal transduction
Disease Progression
Biopsy
Molecular Biology
Signal Transduction
Cell Cycle

Keywords

  • Cell cycle
  • EGFR
  • Molecular targets
  • PPPM
  • Predictive preventive personalized medicine
  • Signal transduction
  • p53

ASJC Scopus subject areas

  • Drug Discovery
  • Health Policy
  • Biochemistry, medical

Cite this

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title = "Targeted therapies for non-HPV-related head and neck cancer: challenges and opportunities in the context of predictive, preventive, and personalized medicine",
abstract = "Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal lining of the upper aerodigestive tract, principally as a result of exposure to carcinogens present in tobacco products and alcohol, with oncogenic papillomaviruses also being recognized as etiological agents in a limited proportion of cases. As such, there is considerable scope for prevention of disease development and progression. However, despite multimodal approaches to treatment, tumor recurrence and metastatic disease are common problems, and clinical outcome is unsatisfactory. As our understanding of the genetics and biochemical aberrations in HNSCC has improved, so the development and use of molecularly targeted drugs to combat the disease have come to the fore. In this article, we review molecular mechanisms that alter signal transduction downstream of the epidermal growth factor receptor (EGFR) as well as those that perturb orderly cell cycle progression, such as p53 mutation, cyclin overexpression, and loss of cyclin-dependent kinase inhibitor function. We outline some of the tactics that have been employed to combat the altered biochemistry. These include blockade of the EGFR using humanized monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib and subsequent generations of TKIs, restoration of p53 function using MIRA compounds, and inhibition of cyclin-dependent kinase and aurora kinase activity using drugs such as palbociclib and alisertib. Knowledge of the underlying molecular mechanisms may be utilizable in order to predict disease behavior and tailor therapeutic interventions in a more personalized approach to improve clinical response. Use of liquid biopsy, omics platforms, and salivary diagnostics hold promise in this regard.",
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AU - Shahoumi, Linah A.

AU - Yeudall, William Andrew

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AB - Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal lining of the upper aerodigestive tract, principally as a result of exposure to carcinogens present in tobacco products and alcohol, with oncogenic papillomaviruses also being recognized as etiological agents in a limited proportion of cases. As such, there is considerable scope for prevention of disease development and progression. However, despite multimodal approaches to treatment, tumor recurrence and metastatic disease are common problems, and clinical outcome is unsatisfactory. As our understanding of the genetics and biochemical aberrations in HNSCC has improved, so the development and use of molecularly targeted drugs to combat the disease have come to the fore. In this article, we review molecular mechanisms that alter signal transduction downstream of the epidermal growth factor receptor (EGFR) as well as those that perturb orderly cell cycle progression, such as p53 mutation, cyclin overexpression, and loss of cyclin-dependent kinase inhibitor function. We outline some of the tactics that have been employed to combat the altered biochemistry. These include blockade of the EGFR using humanized monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib and subsequent generations of TKIs, restoration of p53 function using MIRA compounds, and inhibition of cyclin-dependent kinase and aurora kinase activity using drugs such as palbociclib and alisertib. Knowledge of the underlying molecular mechanisms may be utilizable in order to predict disease behavior and tailor therapeutic interventions in a more personalized approach to improve clinical response. Use of liquid biopsy, omics platforms, and salivary diagnostics hold promise in this regard.

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