Head and Neck Cancer – a major cause of global mortality
Head and neck cancer (HNC) is the sixth most common cancer worldwide and remains a major cause of global mortality. HNC refers to a collection of cancers that arise in the oral, nasal, larynx and pharynx(throat) regions of the head and neck. The majority of these arise in the cells that line the moist surfaces, known as squamous cells. HNC is treated with a number of approaches depending on the type, site, and severity of the cancer. The main treatments include:
+ Targeted therapy against the epidermal growth factor receptor (Erbitux); and
+ Immunotherapy (Keytruda)
When detected early HNC can be effectively treated with surgery alone. However, ~45% of HNCs have already spread to lymph nodes or distant organs at the time of diagnosis. Despite advances in treatment modalities, the prognosis for many HNC patients that present with this form of advanced disease remains poor. The epidermal growth factor receptor (EGFR) is overexpressed in greater than 80% of all HNCs and is an independent predictor of poor treatment outcome. EGFR signalling activates a network of downstream pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, and MAPK pathways, which promote cancer cell growth, survival, invasion, and metastasis (spread to other sites). Consequently, the EGFR has emerged as a major therapeutic target in HNC. Targeted treatments such as monoclonal antibodies and tyrosine kinase inhibitors (TKIs) against EGFR initially held much promise in the treatment of HNC, but have only demonstrated limited responses in patients. This highlights the need for new therapeutic approaches in patients with advanced HNC, with particular focus on patients with resistance to current therapies.
miR-7 and HNC
microRNAs (miRNAs) are small molecules that act by binding to target sequences of a messenger RNA (mRNA) and results in “killing of the messenger”. Altered miRNA expression is common in cancer, classed as either tumor suppressor or oncogenic, depending on their expression levels (amount present) within the tumor and the nature of their mRNA targets. Many miRNAs are aberrantly expressed in HNC and some have considerable potential as biomarkers. We, and others, have shown previously that miR-7 is a highly effective tumor suppressor in multiple cancers via its capacity to downregulate multiple messenger molecules from numerous signalling pathways and at multiple levels within the same signalling pathway. Through targeting oncogenic molecules such as EGFR, Akt, NF-κB subunit (RelA), IRS2, and IGF1R, with miR-7 leads to decreased viability, migration and invasion of various cancers. We have also previously shown miR-7 acts synergistically with the EGFR TKI erlotinib reducing viability of an intrinsically erlotinib-resistant HNC cell line, thus highlighting its therapeutic potential alone and in combination with current therapeutic agents. These proof-of-concept data provide the foundation to explore the potential of mRx-7 for treatment of advanced HNC.