Novel, rationally designed combination strategies, based on genomic and proteomic analyses, to enhance the response to cetuximab therapy in head and neck cancer.

Development of therapeutic resistance poses a challenging problem and limits the success of cancer therapies in the clinic. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is currently used for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) as well as recurrent/metastatic HNSCC. However, 5-year survival rates remain low.In this project, we will focus on the identification of novel combination therapies to overcome cetuximab resistance. Targets for the combination will be identified through genetic and proteomic analysis of the molecular profile of the tumour. We hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy combining (i) cetuximab with (ii) radiotherapy and (iii) an additional molecularly targeted agent, can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. We will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. The potential of these combination therapies will be investigated in vitro on a well-established, comprehensive panel of HNSCC cell lines with different sensitivities to cetuximab. Synergistic combinations will be validated under hypoxia and in 3D spheroids. Next, the most promising combination strategy will be investigated in vivo in HNSCC patient-derived xenograft (PDX) mouse models. The biological and therapeutic implications of our study hold great promise for clinical translation in patients with HNSCC.

Keywords:CANCER THERAPY, COMBINATION THERAPY, TARGETED THERAPY, THERAPY RESISTANCE

Disciplines:Cancer biology, Cancer therapy