Squamous cell carcinoma of the head and neck (SCCHN) represents the eighth leading cause of cancer worldwide. Despite recent advances in surgery and radiotherapy, overall cure is achieved in less than 50% of patients. In contrast to many other cancers, distant metastases are rarely present at diagnosis, but due to better local control, the incidence of systemic spread is rapidly increasing. Those with recurrent or metastatic disease have a poor prognosis, with median survival rates of 6-10 months [1]. Systemic chemotherapy remains the only effective treatment option, but it is associated with significant toxicity rates in HNSCC patients, who usually have a high prevalence of co-morbidities and problematic lifestyle habits [2]. Therefore, additional treatment options that have the potential to improve outcome and that show a toxicity profile different from cytotoxic agents are desperately needed to complement presently available treatment tools.

New agents that specifically target cellular pathways associated with carcinogenesis are promising candidates, because they are already successfully used in other hematological malignancies as well as in solid tumours, such as colorectal or lung cancer [3].

Two primary strategies that might have the potential to change clinical routine within the near future will be discussed in this review: first, blocking epidermal growth factor-based cellular signalling (EGFR-associated) and second, blocking angiogenesis related cellular signalling (VEGFR-associated). In addition, we will review data on new drugs that target molecular targets other than EGFR and VEGF and discuss their relevance for HNSCC treatment.

The EGF-R is a member of the human epidermal receptor (HER)/Erb-B family, a group of tyrosine kinases that transduce extracellular signals to intracellular responses influencing cell proliferation, apoptosis, angiogenesis, and the capacity of tumour cells to metastasize [4]. It has been shown that EGF-R and TGF-α, one of the seven known ligands of EGF-R, are overexpressed in many solid tumours, including colorectal cancer, NSCLC, and HNSCC [5]. Furthermore, EGF-R-overexpression as well as increased m-RNA levels of TGF-α in tumours are usually associated with poorer responses to radiotherapy and have been shown to be strong predictors of decreased disease-free survival [6]. These observations are the rationale for the development of EGF-R-targeted therapies, which are intended to interrupt EGF-R-mediated pathways.

Among EGF-R-targeting therapies, there are two large categories of molecules: monoclonal antibodies, which recognize the ligand-binding domain and interfere with receptor activation, and tyrosine kinase inhibitors which bind to the cytoplasmatic region and influence with downstream signalling events.

Similar to other solid tumours, angiogenesis plays an important role in the pathogenesis of HNSCC. Vascular endothelial growth factors (VEGF) and its receptors are expressed in most cases of HNSCC, and multiple preclinical studies have shown that these markers are associated with tumour progression, changes in microvessel density, and development of lymph node metastasis. In addition, increased levels of VEGF in serum of patients with HNSCC appear to induce tumour growth, metastasis, and treatment failure [22]. Nude mice experiments have shown that inhibition of VEGF pathways markedly decreases angiogenesis and tumour growth [23]. Therefore several strategies to target VEGF-mediated angiogenesis have been developed and are currently being explored in clinical trials.

Src kinases are involved in the regulation of a variety of normal cellular signal transduction pathways, and they influence cell proliferation, survival, angiogenesis, migration, and adhesion. In general, levels of Src expression or activation in epithelial tumours correlate with disease progression. It is important that Src activation results in potentiation of EGF-R-mediated tumour growth by stimulating the same downstream pathways like FAK, STAT, and PI3K[26]. In fact, recently published in vitro experiments show that Src family kinases are highly activated in cetuximab-resistant cells and that they enhance EGF-R activation despite the cetuximab-bound receptor. In these experiments inhibition of Src kinases in originally cetuximab-resistant cell lines resulted in a regaining of sensitivity against cetuximab, indicating a close interaction between Src and EGF-R regarding the processes causing cetuximab resistance in tumour cells [27].

Dual targeted treatment approaches directed at both EGF-R and Src might, therefore, be a feasible strategy for overcoming or preventing acquired resistance to cetuximab.

Dasatinib is a potent inhibitor of multiple oncogenic kinases including Src, cKIT, BCR-ABL, PDGFR, and ephrin A. Because of its ability to inhibit BCR-ABL, it was approved for treatment of chronic myeloid leukemia in 2006. Currently dasatinib is being evaluated in phase I clinical trials for solid tumours either alone or in combination with cetuximab [28].

Proteasomes are proteinases, which play a critical role in degradation of the proteins responsible for the control of cell growth. Inhibitors of proteasomes have demonstrated antitumour effects associated with the induction of apoptosis and sensitization of malignant cells to conventional cytotoxic drugs. Bortezomib, a small molecule inhibitor of proteasomes, has shown efficacy against myeloma and lymphomas, and was recently tested in phase II trials in HNSCC in combination with docetaxel or irinotecan, respectively[29]. Preliminary results have shown 50% disease control rates in recurrent or metastasizing HNSCC patients with the use of low-dose bortezomib[30]. Phase III trials with optimized dosing schedules are needed to confirm these promising new treatment options, which were usually associated with acceptable toxicity.

Molecular targeted therapies are promising novel treatment options for patients with HNSCC. While EGFR-targeting approaches have shown significant but limited efficacy and are already approved for treatment in advanced HNSCC, other options, such as inhibitors of antiangiogenesis, proteasomes, or multifunctional tyrosine kinases are currently evaluated in phase I or II studies, either as single agent treatment or in combination with conventional cytotoxic drugs. Though multiple questions regarding dosing, combination and patient selection need to be answered, molecular targeted treatment will complement conventional chemo- and radiation therapy in patients with HNSCC in the near future. Especially the low toxicity profiles of these new agents are very promising. So far however, all molecular targeted therapies with the exception of cetuximab should be used in the context of clinical trials only.