Research Highlights of 2016–2017

Research at the ZMB focuses on Oncology, Immunology, Infectious Diseases and Transplantation, and Molecular and Chemical Cell Biology. Examples of projects from each of these areas are presented in the following sections.

Oncology

The concept behind the Oncology research programme is to understand fundamental processes in tumour biology in order to develop new molecularly defined and rationally applied cancer treatment methods. Participating researchers from the fields of biology and experimental and clinical medicine approach tumours as biological systems and “neo-organs” in their research. Many different approaches, experimental systems and methods are available for analysing tumour development, growth, progression and tumour cell migration.

Oncology research is one of the main research priorities of the UK Essen and the Faculty of Medicine. The West German Cancer Centre (WTZ) provides the central framework for clinical, translational and basic research in this area and has been funded continuously since 2009 by Deutsche Krebshilfe (German Cancer Aid) as one of its Oncology Centers of Excellence. It was last re-certified in 2016. The WTZ has become one of the leading Comprehensive Cancer Centers in Europe and is one of seven nationwide sites of the German Cancer Consortium (DKTK); the latter was established in 2012 and, together with the German Cancer Research Center Heidelberg (DKFZ), makes up the German Centre for Health Research (DZG) in translational cancer research, which is funded by the Federal Ministry of Education and Research (BMBF) and the hosting state governments.

The Department of Medical Oncology, led by Prof. Martin Schuler, is the largest university institution for medical oncology in Germany and celebrated its 50th anniversary in 2017. The research interests of Prof. Schuler’s Medical Oncology group lie in the development of new molecular strategies for individual, specific and ultra-efficient cancer therapies. Employing modern approaches, the group members seek to identify cellular mechanisms and targets that influence the efficacy of or resistance to different cancer therapeutics. For instance, working closely with their ZMB colleagues Prof. Sven Brandau (Ear, Nose and Throat Clinic), Prof. Karl S. Lang (Institute of Immunology) and other colleagues from Essen and Berlin, they have been able to develop a new therapeutic approach that induces strong and long-lasting immune activation, which marks a major advance in immunotherapy.

Research work and studies on new therapy options for lung carcinoma and metastatic lung cancer have also met with great interest among experts worldwide. This includes one of the most highly regarded and cited medical articles on lung cancer of recent years, which appeared in the Journal of Clinical Oncology on work relating to the use of the targeted therapy Afatinib as a new treatment method other than chemotherapy for patients with EGFR mutations. Follow-up work in 2016 analysing the treatment data of patients whose lung cancer had already spread to the brain showed that Afatinib is a very effective method of treatment and superior to chemotherapy.

Researchers in the group of Prof. Alexander Schramm (Molecular Oncology), together with Prof. Elke Cario (Clinic of Gastroenterology and Hepatology) and PD Dr. Henning Reis (Institute of Pathology), have developed a new model for MYCN-dependent neuroendocrine tumour formation. In Oncotarget they describe how effectively tumours can be combated if tumour growth depends on the activity of an oncogene like MYCN.

Since 2017 Dr. Barbara Grüner (33) has been leading a junior research group for Molecular Tumour Pathology of the DKTK at the WTZ in Prof. Jens Siveke’s Division of Solid Tumor Translational Oncology, where she works closely with the Department of Medical Oncology. She was accepted onto the prestigious Emmy Noether Programme of the German Research Foundation (DFG) in 2017 for her excellent research. Her main interests are in mechanisms of metastasis in pancreatic and lung carcinoma and therapeutic intervention. A novel high-throughput screening method developed by Grüner makes it possible, for the first time, to test the action of hundreds of newly synthesised and established drugs in metastasising cancer cells, now in the living organism.

Immunotherapy is currently one of the most promising methods of treatment for a number of types of skin cancer, including the aggressive and, on account of its viral or UV-associated carcinogenesis, highly immunogenic Merkel cell carcinoma. Prof. Jürgen Becker (Translational Skin Cancer Research) has now been able to show with US colleagues that “epigenetic silencing” suppresses certain genes that are involved in the presentation of tumour antigens (HLA class I) on the surfaces of cancer cells, which prevents the immune system from recognising the tumour cells. This mechanism can be reversed by equipping the tumour cells with the missing modified antigens or by blockading histone deacetylase, the key enzyme responsible for inactivation. Restoring the presentation of the HLA class I antigens on Merkel cell carcinoma cells is an interesting starting point for improved therapies that stimulate the adaptive immune response. This could lead the way to significantly more effective immunotherapeutic approaches in skin cancer.

The Department of Dermatology at UK Essen is known far beyond the local region for its expertise in the area of skin cancer research. It has been led since 2008 by Prof. Dirk Schadendorf, who has also been director of the WTZ at UK Essen since May 2013. The Department specialises in translational issues relating to various aspects of dermato-oncology, particularly tumour immunology and vascular oncology.

PD Dr. Annette Paschen (Molecular Tumour Immunology) and her group study the molecular mechanisms of immune escape that hinder the detection of malignant human melanoma by NK and T cells. Knowledge of these mechanisms provides insights into resistance among some patients to immunotherapy and thereby helps to further optimise immunotherapeutic treatment regimens. On the assumption that interferon gamma (IFNγ), a messenger substance which is secreted by immune cells (CD8+ T cells), is crucial to the effectiveness of therapy due to its antiproliferative and pro-apoptotic effects on tumour cells, the Paschen research group has been working in collaboration with scientists including ZMB colleagues Prof. Ludger Klein-Hitpass, Prof. Astrid M. Westendorf and Prof. Dirk Schadendorf on the evolution of genetic variants in melanoma with disrupted cytokine signalling. Their study was able to prove that genetic evolution of IFNγ resistance is possible in different melanoma patient models.

PD Dr. Iris Helfrich (Vascular Oncology and Metastasis group) and her team are interested in understanding the multifactor stages of melanoma metastasis and the reciprocal communication of tumour cells with cells in the microenvironment in relation to cancer therapy. They were able to show in various studies that tumourinfiltrating cells (e.g. T cells) play a key role in tumour development.

Selected current research projects:

Central to the research of Priority Programme THYROID TRANS ACT (SPP 1629) are new concepts relating to the effects of thyroid hormones and how to distinguish between healthy and diseased thyroid function. One of the three coordinators of SPP 1629 at 14 research locations in Germany is Prof. Dagmar Führer, director of the Institute of Endocrinology and Metabolism at Essen University Hospital.

Led by Prof. Jens Siveke (Translational Oncology (Thoracic and Visceral) and West German Cancer Center) and with other participating locations, scientists are researching how resistance to therapy can be prevented in pancreatic cancer in a consortium project funded by German Cancer Aid, “Regulatoren von Tumorplastizität als therapeutische Zielstrukturen beim Duktalen Pankreaskarzinom” (Regulators of tumour plasticity as therapeutic target structures in pancreatic ductal adenocarcinoma). In its work the consortium combines the latest chromatin and genome analysis techniques with targeted drug development.

PD Dr. Iris Helfrich (Clinic for Dermatology, Vascular Oncology and Metastasis group) is working with colleagues from the University of Wuppertal, RUB and the Lead Discovery Center in Dortmund on the “RIST – Ras Inhibition in soliden Tumoren” (Ras inhibitors in solid tumours) consortium project, which is receiving funds from the European Regional Development Fund (ERDF) through the European Union and the State of North Rhine-Westphalia (NRW). The group of experts from molecular biology, protein structure research, chemical drug design and medical testing systems are aiming for preclinical development of a pharmaceutical agent to specifically and effectively inhibit Ras proteins. The RIST project is laying the groundwork for the use of selective drugs to fight important types of cancer that are attributable to mutations in the Ras genes.

Research Training Group GRK 1739 “Molecular Determinants of the Cellular Radiation Response and their Potential for Response modulation”, coordinated by Prof. Verena Jendrossek (Institute of Cell Biology), is now in its second funding period following a positive evaluation and extension by the DFG. Radiation therapy is one of the most important and effective therapeutic options in cancer treatment; the group is therefore working to explain cellular reactions and achieve a mechanistic understanding of cell response to ionising radiation so as to better understand radiation sensitivity. In its work it combines innovative concepts and the latest methods in radiobiology, experimental and clinical (radio)oncology and biomedicine. The EU-funded Marie Sklodowska Curie Innovative Training Network “RADIATE”, of which Verena Jendrossek is co-coordinator, addresses these issues on an international level.

Similar questions are dealt with in the national consortium “ZiSStrans – Zielstrukturen der individuellen Strahlenempfindlichkeit” (Targets of individual radiation sensitivity), in which Prof. Verena Jendrossek (Molecular Cell Biology research group) and six partner institutions at six different locations are involved. The BMBF is funding this translational research project on personalised radiotherapy for head, neck and throat cancer as the successor to the BMBF consortium “ZISS – Identification of molecular targets and signaling networks that modulate radiation hypersensitivity and radiation resistance”. It sets out to examine how the reaction of tumour tissue to radiotherapy can be influenced without the unwanted side effects that generally make it difficult to continue with the therapy.

With funding from German Cancer Aid, Prof. Ralf Küppers (Institute of Cell Biology (Tumour Research)) is working with colleagues from Frankfurt am Main to examine which cancer-causing genetic defects are responsible for combination lymphomas and how double lymph node cancer occurs.

Prof. Katharina Fleischhauer (Institute for Experimental Cellular Therapy), with colleagues from the University Hospitals of Hamburg, Dresden and Würzburg and the Helios Clinic in Wiesbaden, and with funding from the German José Carreras Leukaemia Foundation, is exploring how the selection of suitable donors for bone marrow transplants can be improved and the risks and side effects minimised. Central to their research is the tissue marker HLADP, which the latest findings have shown to significantly reduce the risk of relapse without an equivalent rise in other complications where there is a match between donor and recipient. In the study, a search will now be made before treatment specifically for the same HLA-DP group donors in order to find out whether this increases the chances of survival and fewer relapses occur.

Maintaining the benefits of transplanted somatic stem cells without side effects is the goal in another project, “SEVRIT – Production and Quality Assurances of Stem Cell-Derived Extra Cellular Vesicles for Novel Regenerative and Immunomodulatory Therapeutic Approaches”, led by Prof. Peter Horn (Institute of Transfusion Medicine) and colleagues. Funded under the lead market competition LifeSciences.NRW of the EU and the state government, the project explores whether the same therapeutic success can be achieved by transplanting only the extracellular vesicles (EV) rather than the stem cells themselves.

Prof. Dirk Schadendorf (director of the WTZ, Clinic for Dermatology) and colleagues from the DKTK in Tübingen and Heidelberg are investigating specific mutations of cancer cell genomes as part of a three-year DKTK Joint Funding competition. The project promises to deliver new insights into the causes of gene mutations which are responsible for the development of cancer, cell proliferation and the resulting tumours. Genetic tumour analysis has hitherto always concentrated on mutations that result in changes to the coding information of genes and therefore to altered proteins. This project goes an important step further and looks specifically for mutations in cancer cell genomes that are located in non-coding regions.