Despite better treatment options, outcomes for patients with head and neck cancers have not substantially improved over the past several decades. Historically a tobacco- and alcohol-associated cancer, the epidemiology of head and neck cancer has shifted in recent years to reflect an increase in human papillomavirus (HPV)-driven tumors.
Next-generation sequencing efforts focusing on the most common form, head and neck squamous cell carcinoma (HNSCC), are illuminating the hidden complexities of its genome. Multiple molecular subtypes and key differences between tumors with and without HPV infection are beginning to emerge. The challenge ahead is to find ways to use this molecular blueprint to guide more personalized and effective therapies for individual patient populations.
Resisting Improved Outcomes
Head and neck cancers are a group of heterogeneous malignancies that develop in a common anatomic region, with an incidence 600,000 cases per year worldwide including 50,000 annually in the United States. The vast majority are HNSCCs arising in the epithelial cells that line the mucosal surfaces of the head and neck.
Outcomes for the substantial number of patients who present with advanced disease have remained stubbornly low for the past several decades, despite improvements in treatment options, including the development of molecularly targeted therapies. In particular, drugs targeting the epidermal growth factor receptor (EGFR) have been a central focus of research and development, given that this protein is overexpressed in more than 90% of HNSCCs.
Although research efforts culminated with the FDA’s approval of cetuximab (Erbitux) in 2006, other EGFR-targeting therapies have proved clinically disappointing and cetuximab remains the only targeted agent approved for HNSCC. Cetuximab has demonstrated improvements in overall survival compared with standard therapies; it is indicated as a single agent and in combination with radiation or platinum-based therapy in initial and recurrent HNSCC treatment settings.
Turning to Next-Generation Sequencing
The success of targeted therapies in HNSCC has been tempered by a poor understanding of the genomic background of this disease but with the advent of next-generation sequencing technologies, that is beginning to change.
Landmark studies published in 2011 identified common somatic mutations, some linked to HNSCC for the first time, providing valuable insight into HNSCC carcinogenesis.
Commonly mutated genes were TP53, FAT1, CDKN2A, PIK3CA, NOTCH1
, and CASP8
. The tumor suppressor gene TP53
, frequently described as the “guardian of the genome” since its primary function is maintaining genomic integrity, is a transcription factor that regulates the expression of a whole host of target genes. It is the most frequently mutated gene in cancer and had long been suspected to be involved in the development of HNSCC.FAT1
are also tumor suppressor genes. FAT1
is involved in the Wnt signaling pathway, binding to Wnt and limiting its ability to translocate into the nucleus. CDKN2A
encodes the p16 protein that is an inhibitor of cyclin-dependent kinases (CDKs), which play a vital role in the normal progression of the cell cycle. CASP8 encodes a caspase enzyme involved in programmed cell death. A key novel finding was frequent mutations in the NOTCH1
gene, which encodes a receptor involved in embryonic development and cellular differentiation.
Ligand binding to the Notch receptor
drives a cascade of cleavage events that ultimately release a portion of the receptor that is inside the cell membrane, known as the notch intracellular domain (NICD). The NICD then moves into the nucleus where it activates numerous genes. Depending upon the cellular context, Notch1 can act to either promote cancer cell growth or to suppress it, but in the case of HNSCC it is thought to predominantly function as a tumor suppressor.
Tough-to-Target Tumor Suppressors
The picture that began to emerge was that these tumors are characterized by frequent loss of tumor suppressor genes and a paucity of readily targetable driver mutations, making them much less amenable to current therapeutic strategies. Researchers have made some strides in working around the difficulties in targeting tumor suppressor proteins.
Since p16 is upstream of CDK4/6, its loss can drive overexpression of these proteins. As kinases, they present a much more readily druggable target and, indeed, CDK4/6 inhibitors, led by palbociclib (Ibrance), have been developed and are being evaluated in HNSCC (NCT02499120).
Studies are also being conducted to seek out other genes that are specifically required for the survival of cancerous cells with mutations in tumor suppressor genes such as TP53
, a phenomenon known as synthetic lethality. One gene that was identified in this manner is the Wee1 kinase, which plays an important role in the cell cycle. Phase I trials of a Wee1 inhibitor, AZD1775, are ongoing in HNSCC (NCT02508246).