Abstract
Keywords
Head and Neck Cancer
Head and neck cancer encompasses a large and diverse group of tumors with complex etiology and pathobiology that is typically resistant to therapy, particularly when diagnosed in advanced stages. The most common of these tumors are head and neck squamous cell carcinomas (HNSCCs), which are diagnosed in about half a million people and result in a quarter million deaths every year worldwide. Unfortunately, the overall 5-y survival of patients with HNSCC has remained rather low at about 50% to 60% for the past 3 to 4 decades. Lack of more effective therapies has been attributed to late diagnosis and to the intrinsic resistance of HNSCC cells to existing treatment modalities. However, in recent years, the prospect of developing safe and efficient therapies for HNSCC has improved by a deeper understanding of the precise mechanisms underlying the biology of these tumors. This special issue of the Journal of Dental Research brings together leaders in the field who discuss the state of the science in head and neck cancer and present new early diagnostic tools and mechanism-based therapies that might benefit patients with this malignancy.
A Changing Landscape in Head and Neck Etiology
It is well known that tobacco, excessive alcohol consumption, and betel chewing are associated with increased risk for HNSCC. More recently, seminal studies unveiled the role of human papillomavirus (HPV) in the etiology of HNSCC (Gillison et al. 2000; Worden et al. 2008). There is an increasing incidence of HPV-associated HNSCCs, which now account for 20% to 30% of all new cases, most of which arise in the oropharynx. Here, mechanisms of HPV integration in the human cell genome and potential impacts of these processes to the etiology of HNSCC are discussed (Carey et al. 2018). Furthermore, evidence supporting a functional correlation between bacterial infection and HNSCC has emerged in recent years, providing an alternative link between the microbiome and the initiation of HNSCC (Perera et al. 2018). These articles highlight the impact of pathogenic microorganisms on the transformation of oral epithelial cells and the genesis of HNSCC.
Elucidation of the Head and Neck Cancer Oncogenome
With the advent of deep sequencing, seminal work has unveiled the mutational landscape of HNSCC (Agrawal et al. 2011; Stransky et al. 2011). The expansion of this large deep sequencing effort as part of The Cancer Genome Atlas (TCGA) Network (2015) has revealed numerous mutations, copy number variations, and altered DNA methylation profiles in individual HNSCC lesions, thus providing an in-depth genomic characterization of HNSCC. Access to this information has led to the discovery and functional characterization of important signaling pathways that drive the pathobiology of head and neck cancer. Here, the NOTCH (Califano and Fukusumi 2018), Wnt-β-catenin (Kukuruzinska and Alamoud 2018), PI3K (Kemmer et al. 2018), and Calprotectin (Herzberg et al. 2018) signaling pathways are discussed in detail.
New Precision Therapies
For the past 4 decades, therapy for patients with head and neck cancer has been centered on surgery, platinum-based therapies, and radiation. The approval of cetuximab by the Food and Drug Administration (FDA) in 2007 constituted a landmark event in the field, as it became the first targeted therapy for HNSCC. However, cetuximab provides significant benefit only to a relatively small subgroup of patients with head and neck cancer. As such, the search for new, targeted therapies is warranted. Deeper understanding of the HNSCC genomics (Kemmer et al. 2018) has informed the development of precision therapies (Polverini et al. 2018) that hold promise to be more effective and safe than existing ones. In recognition that TP53 is the most frequently mutated gene in HNSCC, new therapies targeting TP53 mutations are being developed and tested (Lindemann et al. 2018). The biological phenomenon of cell plasticity has been characterized as an important feature of the pathobiology of HNSCC, and it is now being explored as a new therapeutic target for head and neck cancers (Jiang et al. 2018).
The Immune Therapy Revolution
In 2016, 2 targeted drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo), were approved for treatment of HNSCC in the United States. These inhibitors of the PD-L1/PD-1 immune checkpoint pathway constitute a conceptual innovation in HNSCC treatment as they kill tumor cells indirectly by enhancing the capacity of the host immune system to recognize and eliminate these cancer cells. As such, immunotherapy has emerged as a novel and promising treatment modality for head and neck cancer (Moskowitz and Ferris 2018). Anti-HNSCC vaccines constitute an alternative approach to harness the host immune response that have been proposed very recently and are in preclinical stages of development (Lei et al. 2018). Of note, the preclinical testing of these therapies requires the continuous development of experimental immunocompetent models that closely resemble human disease. Of particular interest today is the development of animal models that enable accurate testing of new immunotherapies (Young et al. 2018).
Early Diagnosis
The field of head and neck oncology is moving toward precision-based therapies tailored to the unique aspects of the specific tumor of each patient. One of the most clinically significant findings of the past decade is that patients with HPV-positive HNSCC tend to be younger and respond better to therapy than those with HPV-negative tumors. This recognition offered the possibility of treating HPV-positive patients with less invasive surgery (lower morbidity) accompanied by less aggressive systemic therapies and radiation therapy (more tolerable side effects). Importantly, earlier diagnosis by improved detection methods (Nonaka and Wong 2018) can further improve patient outcomes by enabling more conservative treatment of head and neck cancer.
A New Frontier in Head and Neck Cancer Research and Treatment
We are witnessing a revolution in our understanding of HNSCC molecular pathobiology and in the diagnosis and treatment of this malignancy. The work performed by dedicated investigators in many laboratories and the clinic is shining new light on HNSCC initiation and progression, as well as breaking new grounds on the discovery of novel prevention modalities and precision targeted and immune therapies. Collectively, these major research efforts aim at improving the survival and quality of life of patients with head and neck cancer. We are very thankful to all clinicians and scientists around the world for their dedication and commitment to this work, as well as to our colleagues and friends who contributed the manuscripts that are being published in this special issue of the Journal of Dental Research.
Footnotes
The authors received no financial support and declare no potential conflicts of interest with respect to the authorship and/or publication of this article.