Epigenetic alterations in oesophageal carcinoma: The role of microRNAs in determination and prediction of chemo- and radiosensitivity in oesophageal cancer and its meaning for response control of neoadjuvant therapy

Neoadjuvant treatment is nowadays a standard therapy for patients with locally advanced oesophageal carcinoma and improves the overall survival in those patients who respond to this therapeutic modality. But only about 40 % of patients respond to this preoperative treatment. Monitoring of the success of this treatment, which is currently based on histological, endoscopical and radiological assessments, is insufficient. Epigenetic changes have important roles in cancer development and treatment. In this context microRNAs have been shown to be useful biomarkers for classifying cancers and providing information about chemo- and radiosensitivity of various cancer types. Hence, the goal of this proposal is to investigate the role of microRNAs in prediction of chemo-/ radiosensitivity in oesophageal cancer and in the monitoring of the success of a neoadjuvant therapy in these patients. Therefore we use cell culture models and human pre- and posttherapeutic samples to determine the microRNA expression profiles before and after neoadjuvant therapy. Furthermore, we aim to identify likely target genes of the altered microRNAs. This will allow us to get a better insight into cellular processes which affect sensitivity to a neoadjuvant treatment. With these results we hope to provide a perspective for new diagnostic and therapeutic approaches that can affect neoadjuvant treatment in oesophageal cancer.

The current scholarship provided the unique opportunity for the applicant to work in the highly experienced and efficient Upper GI Laboratory of the Surgical Department at Flinders University/Adelaide/Australia. Based on the excellent support of the team in Adelaide, the applicant was able to work successfully on all parts of his project. We could finally answer all hypotheses formulated in the initial proposal despite of the limitation to only investigate miRNAs in the context of chemotherapy in oesophageal cancer. Especially the adaptation of the research programme, which was mainly based on the experience of our partners in the respective research fields, allowed a more detailed analysis of the primary questions. Taken together, we were able to generate the initially mentioned molecular database that provides a number of miRNAs which potentially play a crucial role in chemotherapy response and resistance in oesophageal cancer. We could show in in-vitro and in-vivo experiments that miRNA profiling is indeed an adequate tool to determine and predict chemo-sensitivity in oesophageal adenocarcinoma and squamous cell carcinoma. Furthermore, we confirmed that chemotherapy itself affects miRNA expression in cell culture experiments implicating that miRNA expression profiling is as well an adequate tool to monitor the success of neoadjuvant treatment of oesophageal tumours. In addition, we identified several intracellular pathways such as KRAS or others which are deregulated in drug resistant cells highlighting these pathways as potential targets of the identified deregulated miRNAs in these resistant cell lines. Finally, we demonstrated in a first project that ectopic miRNA modulation impacts on the oesophageal cancer cells’ response to cisplatin and 5-FU. This part supports the emerging role of miRNAs in new therapeutic approaches in the battle against oesophageal cancer. And thirdly, the extension of the initial research programme and the inclusion of several new techniques such as work with tumor-derived exosomes finally led to the chance for the applicant to prepare his further research work in Germany. The expertise in these additional techniques, which were not primarily necessary to answer the questions formulated in the initial proposal, allowed the development of a profound follow-up research programme.