Identifying rational combination therapies to overcome intrinsic and acquired resistance to EGFR-targeting agents.

The introduction of targeted therapies is now at the forefront of personalised medicine in cancer treatment. After the initial promise of targeted therapies, drug resistance is however emerging as the major obstacle to progress in this field. In this project, we will focus on identification of new combination therapies to overcome intrinsic and acquired resistance to cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Hereby, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. First, we will screen for new drug combinations by next-generation whole-exome sequencing and tumour kinome profiling of cetuximab-sensitive versus -resistant (intrinsic and acquired) HNSCC cell lines. Next, based on an integrative analysis of both the genetic profile and the kinome profile of cetuximab resistance, new combination treatments can be designed rationally to overcome cetuximab resistance. The molecular pathways underlying the cytotoxic effects of the selected compounds, in combination with chemotherapy and/or irradiation, will be investigated thoroughly, with focus on the hypoxic microenvironment as an important additional cause of therapy resistance. In conclusion, based on our screening results, new combination therapies will be designed rationally in order to thwart resistance to EGFR-targeting agents. Successful combinations will be forwarded into animal studies and ultimately into a clinical trail to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients.

Keywords:COMBINATION THERAPY, ONCOLOGY

Disciplines:Morphological sciences, Oncology