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

Neoadjuvante Therapien sind heutzutage eine Standardtherapie für Patienten mit lokal fortgeschrittenem Ösophaguskarzinom. Allerdings sprechen nur etwa 40 % der PatientInnen und Patienten auf diese präoperative Behandlung an. Die Erfolgskontrolle, die derzeit auf histologischen, endoskopischen und radiologischen Untersuchungen basiert, ist noch unzureichend. Epigenetische Veränderungen spielen eine wichtige Rolle bei der Krebsentstehung und -behandlung. In diesem Zusammenhang haben sich microRNAs als nützliche Biomarker für die Klassifizierung von Krebserkrankungen und die Bereitstellung von Informationen über die Chemo- und Strahlensensitivität verschiedener Krebsarten erwiesen. Ziel dieses Projektes ist es daher, die Rolle von microRNAs bei der Vorhersage der Chemo-/Strahlensensitivität bei Speiseröhrenkrebs und bei der Erfolgskontrolle einer neoadjuvanten Therapie zu untersuchen. Dazu verwenden wir Zellkulturmodelle und humane prä- und posttherapeutische Proben, um die microRNA-Expressionsprofile vor und nach der neoadjuvanten Therapie zu bestimmen. Darüber hinaus wollen wir mögliche Zielgene der veränderten microRNAs identifizieren. Dies ermöglicht uns einen besseren Einblick in zelluläre Prozesse, die die Sensitivität gegenüber einer neoadjuvanten Behandlung beeinflussen. Mit diesen Ergebnissen hoffen wir, neue diagnostische und therapeutische Ansätze für die neoadjuvante Behandlung von Speiseröhrenkrebs zu entwickeln.

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.