The relevance of Her receptor ligands for the trastuzumab and cetuximab resistance in gastric cancer

• Applicant: Dr. Julia Esther Kneißl
• Subject Area: Pathology ; Cell Biology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225898597

For gastric cancer, only limited therapeutic options are available. The Her receptors play an important role in the regulation of tumor-relevant processes. The activity of the receptors is controlled via binding of a group of specific ligands. As Her receptors are often overexpressed in tumors, they represent an ideal target for therapeutic intervention. The monoclonal antibodies trastuzumab and cetuximab are directed against Her receptors. These antibodies are effective in the treatment of gastric cancer in combination with chemotherapy. Nevertheless, like for all other tumour-therapies, there is the problem of therapy resistance. Recent research based on cancers, unrelated to gastric cancer, showed an important role of the Her receptor ligands for mediating the resistance against trastuzumab and cetuximab. However, for gastric cancer, this aspect has hardly been investigated. Therefore, this project concentrates on the analysis of the relevance of five Her receptor ligands (amphiregulin, epidermal growth factor, heparin-binding epidermal growth factor, heregulin, transforming growth factor alpha) for the resistance against trastuzumab- and cetuximab-based therapies in gastric cancer. This topic will be analyzed by extensive in vitro-studies on gastric cancer cell lines. Furthermore, the regulation of the ligand expression with specific focus on microRNAs will be investigated. Based on these findings, options for a therapeutic intervention will be tested in vitro. Finally, the ligand profile in human gastric tumour samples will be determined and correlated to histopathological data. The value of the Her ligands for the prediction of the cetuximab response will be investigated by analysis of pre-therapeutic tumors of patients treated with cetuximab in combination with chemotherapy. Taken together, I expect that this project will contribute substantially to the understanding of the relevance of Her receptor ligands for the resistance to trastuzumab and cetuximab in gastric carcinoma.

• DFG Programme: Research Grants