Machanismen der Radiosensitivierung von Tumorzellen bei Inhibition des EGF-Rezeptors

• Applicant: Professor Dr. Ekkehard Dikomey
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2007 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 38048311

The inhibition of the epidermal growth factor receptor (EGFR) by the monoclonal antibody cetuximab is already successfully used in the clinics to increase the treatment efficiency of head and neck squamous cell carcinoma (HNSCC) by radiotherapy. However, not all patients will actually benefit from this approach. This is also demonstrated by own data achieved within the first grant period. Efficient radiosensitization by cetuximab was only observed in few of the cell lines investigated, both for cell cultures as well as xenografts. Likewise, a clear correlation between EGFR expression and cellular radiosensitivity was only observed for a specific subgroup of HNSCC cell lines. Therefore, it is necessary to unveil the specific mechanisms, by which the cellular radiosensitivity is modulated by EGFR (1) and also to identify the parameters under which cetuximab will actually result in efficient radiosensitization (2). Within the first grant period we were able to unravel some essential details about the interaction between EGFR dependent signalling cascades, DNA double strand break (DSB) as well as cell cycle regulation after irradiation. Based on these data we are aiming to establish biomarkers, which will allow to identify tumours that can actually be radiosensitized by cetuximab. Due to the actual relevance in radiotherapy we will also investigate the effect of cetuximab in combination with radio-chemotherapy using cisplatin (3) and, additionally, its effect in HPV infected HNSCC tumour cells (4). Based on these findings new models for individualized anti-EGFR therapy shall be developed to improve the therapy of HNSCC patients.Summary of the central questions:1) By what mechanisms does the EGFR regulate the cellular radiosensitivity?2) Which mechanisms predict the radiosensitization by cetuximab?3) What is the combined effect of cetuximab together with cisplatin?4) Does a HPV infection influence the radiosensitization of HNSCC cells by EGFR inhibition?

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Jochen Dahm-Daphi; Dr. Ursula Kasten-Pisula