Targeted Therapy in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (LA-R/M HNSCC)

Abstract

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.

Keywords: EGFR; HNSCC; SCCHN; cetuximab; signal transduction.

Figure 1

The function of p16/CDKN2A. Cyclin D activates CDK4/6, which phosphorylates Rb, inactivating it. Release of the transcription factor E2F activates cell progression. p16 inhibits CDK4/6 to block cell progression. CDK: cyclin-dependent kinase, Rb: retinoblastoma.

Figure 2

p53 regulation. p53 is a tumour suppressor gene that is activated by a mitogen (via ARF/p14) or genotoxic (ATM) damage. MDM2 inhibits p53 and promotes p53 degradation by ubiquitination.

Figure 3

The main pathways involved in HNSCC. TKR: tyrosine kinase receptor, VEFGR: vascular endothelial growth factor receptor, EGFR: epidermal growth factor receptor, HER2: human epidermal growth factor receptor 2, PI3K: phosphatidylinositol 3 kinase, mTOR: mammalian target of rapamycin, MAPK: mitogen-activated protein kinase.

Figure 4

The interaction between T-cell receptors (TCRs) and major histocompatibility (MHC) molecules expressed on antigen-presenting cells (APCs) is the first event that leads to T cell activation. This occurs primarily in the lymph nodes. A subsequent interaction between the CD28 receptors on T-cells with B7 co-stimulatory molecules on APCs completes T cell activation. CTLA-4 and PD-1 are negative regulators of T cell immune responses, and they are required to avoid excessive immune activity. CTLA-4 binds to B7 and therefore competes with CD28. It seems to act early during T cell activation in the lymph nodes. PD-1 binds PDL-1 and PDL-2, which are both negative modulators of immune T cell responses. The role of PD-1 inhibitory activity seems to be more important in peripheral tissues during the effector phase. Anti-CTLA-4 and anti-PD-1 antibodies block these inhibitory checkpoints, thereby enhancing antitumour immune activity.