Max Eder Working Group on Experimental Paediatric Oncology
The Max Eder Working Group on Experimental Paediatric Oncology focuses in particular on the mechanisms of tumour development in children. To this end, we use new genomic characterisation techniques. One focus is on cancers characterised by changes in the SWI/SNF complex.  

In many tumours, individual components of this complex (such as the SMARCB1 or SMARCA4 proteins) are affected by inactivating mutations or deletions (loss of genetic material). Common examples in children and adolescents are rhabdoid tumours, in which SMARCB1 is deleted in the majority of cases, but SMARCB1-deficient (so-called epithelioid) sarcomas and kidney tumours also occur. The University Hospital of Augsburg is home to the EU-RHAB Registry and the SIOPE ATRT 01 study (led by Prof. Dr. Dr. Frühwald), which focuses on optimising the treatment of these tumours.  

Deletions of the SWI/SNF complex lead to a variety of epigenetic changes that affect both the histone code and the methylation of these tumours. Although the genetic mechanisms behind these diseases are known, only a fraction of the epigenetic changes that cause these tumours have been identified to date. In the past, for example, it has been shown that despite the high genetic homogeneity of rhabdoid tumours of the central nervous system (known as ATRT), there is marked epigenetic heterogeneity, and three clinically relevant subgroups have been identified.

Epithelioid sarcomas and renal medullary carcinomas
In this subproject, we are investigating the epigenetic mechanisms that cause the development of epithelioid sarcomas and renal cell carcinomas. Both diseases are characterised by deletions of SMARCB1 at the genetic level and clinically by high resistance to conventional chemotherapy. Using methylation arrays and ChIP sequencing, we analyse the epigenetic landscape of these tumours in order to identify new therapeutic targets. This is done on both cell lines and primary tissues. In a further step, the target structures identified in the previous analyses are tested on cell lines to determine their suitability as therapeutic targets.    

Molecular characterisation of adrenocortical carcinomas in children and adolescents
Another part of our work is the molecular characterisation of adrenocortical carcinomas in children. Here, we use state-of-the-art methods such as single-cell sequencing, RNA sequencing and methylation diagnostics. We work closely with the GPOH-MET study centre. 

Overall, we see ourselves as a hub for all researchers at the Clinic for Paediatrics and Adolescent Medicine, but also for the entire University Hospital of Augsburg. This primarily concerns support in the analysis of high-throughput data from the epigenetic field. 

Requests for cooperation can be sent to pascal.johann@uk-augsburg.de. 

Team:
Prof. Dr. med Pascal Johann
Victoria Fincke, MSc.
Maurice Lossner, cand.med.
Svenja Steinhauser, cand.med. 

Malignant rhabdoid tumours
Malignant rhabdoid tumours (MRT) are rare, highly aggressive and often very difficult to cure. They predominantly affect infants and young children under the age of three and can manifest even before birth. MRT can occur in almost all anatomical locations. They most commonly affect the central nervous system (CNS) (> 50% in the cerebellum). There they are referred to as ATRT (atypical teratoid rhabdoid tumour). Other common locations are the kidneys (RTK – rhabdoid tumour of the kidney) and soft tissues (eMRT – extrarenal malignant rhabdoid tumour) including cervical, thoracic, hepatic, mediastinal, retroperitoneal, cardiac, pelvic soft tissue, scrotal, vaginal, extremities, lumbosacral or orbital. In almost 100% of rhabdoid tumours, genetic alterations (somatic and/or germline) of the SMARCB1 gene in the chromosome region 22q.11.23 or SMARCA4 (2-3%) in 19p.13.2 are found. At the same time, no additional recurrent genetic mutations have been detected in rhabdoid tumours to date. Rhabdoid tumours belong to the group of malignancies in which germline mutations are most frequently detected. When germline mutations are detected in SMARCB1, this is referred to as rhabdoid tumour predisposition syndrome 1 (RTPS1), and when SMARCA4 germline mutations are detected, this is referred to as RTPS2. 

The EU-RHAB Registry: Globally recognised centre of excellence
The European Rhabdoid Registry was established by Professor Frühwald on behalf of the GPOH and has become well-established both nationally and internationally. It has been based at the University Hospital in Augsburg since 2010. Since 2005, we have been recording comprehensive clinical and genetic data on children with rhabdoid tumours (including RTPS) from Europe and many other countries in the EU-RHAB Registry. We advise clinicians, laboratory doctors and affected families both personally and through expert opinions, and recommend – as part of a Europe-wide clinical care study – a uniform treatment regimen that we have developed specifically for patients with MRT. Since 2005, we have registered more than 450 patients with MRT in EU-RHAB. More than 350 of them were treated in accordance with the EU-RHAB recommendations. This has enabled the competence centre in Augsburg to generate unique clinical expertise based on a comprehensive data set. 

At the heart of the EU-RHAB registry is a network of specialists from clinics, diagnostics and laboratories. Since 2005, the biological materials of all recruited patients (almost 100% recorded in Germany) have been stored in reference institutes for pathology and neuropathology (Professor Vokuhl, Bonn and Professor Hasselblatt, Münster), human genetics and (molecular) cytogenetics (Professor Siebert, Ulm), molecular genetics (Professor Siebert, Ulm) and cerebrospinal fluid analysis (Professor Frühwald, Augsburg). The clinical data of all affected individuals is collected, validated and evaluated at the competence centre in Augsburg (Professor Frühwald). The image data sets are evaluated on a server-based system at reference institutes in Augsburg (Professor Kröncke, extracranial RT, Dr Bison, ATRT). 

The competence centre in Augsburg performs an outstanding service in providing clinical advice to attending clinicians. In close coordination between working groups in Augsburg and Ulm, it also supports the human genetic care of affected families through personal consultations and expert opinions. This ranges from questions about the interpretation of the clinical consequences of mutations and the determination of the probability of recurrence to aspects of family planning. 

By evaluating comprehensive, standardised data on children who have received uniform treatment and through extensive reference diagnostics on biological materials, we have been able to contribute to a significant improvement in our understanding of the fundamental molecular mechanisms. The data in the registry form the basis for the development of improved treatment strategies.
 

Research projects/current study: 

• SIOPE ATRT01: "An international prospective umbrella trial for children with atypical teratoid/rhabdoid tumours (ATRT) including a randomised phase III study evaluating the non-inferiority of three courses of high-dose chemotherapy (HDCT) compared to focal radiotherapy as consolidation therapy. German Childhood Cancer Foundation
     
• RTPS Project: "Families with rhabdoid tumour predisposition syndromes (RTPS1 and 2) – Development of a clinical and human genetic care concept for rhabdoid tumour predisposition syndromes". German Cancer Aid 70113981
     
• Recurrence project: "Mechanisms of progression in malignant rhabdoid tumours". DFG 1516/4-1 SIOPE ATRT01
     

Atypical teratoid, rhabdoid tumours (ATRT) are rare, highly aggressive tumours of the central nervous system (CNS, brain and spinal cord) that mainly affect very young children (usually aged 18-22 months at diagnosis). Over many years, the European Rhabdoid Registry (EU-RHAB) has collected data on more than 450 children and evaluated both genetic and clinical data. All affected children were treated according to a uniform treatment regimen based on expert opinion. The treatment recommendations of the EU-RHAB registry form the basis for the therapy outlined below.   

Some clinically significant questions could not be answered by the EU-RHAB registry analyses. These include the question of whether long-term damage in young children as a result of radiotherapy can be avoided by replacing it with high-dose chemotherapy (HDCT). In order to take a decisive step towards improving therapy, increasing cure rates and at the same time keeping side effect rates as low as possible, an "umbrella concept" (a study consisting of several parts and covering all affected patients) was designed for children with ATRT in Europe: the SIOPE ATRT01 study with three parts: Part A, Part B and Part C. An

integral part of the concept is a randomised clinical study in accordance with Section 4 (23) of the German Medicines Act (Part A). The primary objective of this study is to test the non-inferiority of HDCT compared to radiotherapy for patients aged 12-35 months. After treatment with three courses of chemotherapy, patients are randomly assigned to one of two arms that are not clearly distinguishable in terms of efficacy and side effect profile. To ensure that patients are evenly distributed between the two groups, each patient is randomly assigned to one of the two groups. While the HDCT arm receives three courses of HDCT, patients in the RT arm receive radio-chemotherapy with 12 courses of chemotherapy and parallel radiotherapy. Patients outside Part A (e.g. < 12 or >35 months) are treated with either HDCT (Part B - HDCT) or radiotherapy and 12 courses of conventional chemotherapy (Part C - RT), depending on their risk profile. In Parts B and C, a comparison is made with historical controls (patients from the EU-RHAB registry and other data from the literature).

  Furthermore, neuropsychological examinations are carried out using a specially compiled test battery to assess the development of cognitive dimensions (e.g. memory, concentration) and the quality of life of children and adolescents. The aim is to investigate whether children who receive radiotherapy at a young age are more severely impaired in their mental development after 2, 5 and 10 years than those who have received HDCT.
  SIOPE ATRT01 is the first randomised, controlled clinical trial for children with a primary diagnosis of ATRT in German-speaking and European countries.
All children and adolescents affected by ATRT are to be included in the SIOPE ATRT01 study in order to learn as much as possible about the disease and, above all, about the therapy and its side effects. 

Malignant endocrine tumours (MET) are very rare tumours in children and adolescents and originate from hormone-producing glandular tissue. The course of malignant endocrine tumours is highly variable. METs include adrenocortical tumours (ACT)/carcinomas (ACC), pheochromocytomas (PCC)/paragangliomas (PGL), differentiated (DTC) and medullary thyroid carcinomas (MTC), as well as neuroendocrine tumours (NET) of the gastroenteropancreatic system (GEP). Every year, >80 children and adolescents with malignant endocrine tumours are recorded in the MET registry. 

The MET registry was initiated in 1997 by Prof. Dr. Peter Bucsky in Lübeck. From 2008 to 2021, the registry was managed by Prof. Dr. Peter Vorwerk at the University Children's Hospital in Magdeburg. Since February 2021, the German Paediatric Oncology and Haematology Society (GPOH) has transferred the mandate for the MET registry to Dr Antje Redlich, Magdeburg, as clinical study director and Dr Michaela Kuhlen, Augsburg, as scientific study director. 

The treatment of children and adolescents with MET is interdisciplinary. Due to the rarity of these tumours, treating physicians have a high need for consultation throughout the entire diagnostic and therapeutic process. A network of specialists from clinics, diagnostics and laboratories is available for consultation. More than 1,400 patients have now been registered in the MET registry. This provides unique clinical expertise based on this comprehensive clinical data set, which also forms the basis for consultation and the development of improved diagnostic and therapeutic strategies. 

Localised, completely removed METs usually have a good prognosis. Here, the reduction of complications and therapy-related long-term effects must be important goals in the further development of treatment and aftercare concepts. An important step in this direction is the establishment of a "Reference Centre for Nuclear Medicine" at the Clinic for Nuclear Medicine at the University Hospital of Giessen/Marburg to standardise radioiodine therapy and, in the long term, to record and reduce late effects in children and adolescents with differentiated thyroid carcinomas. 

High-risk patients (e.g. locally advanced and metastatic ACC, MTC, PCC/PGL) still have a poor prognosis today. Innovative treatment concepts are needed for these patients. Due to the rarity of the tumours and the associated low number of patients, clinical studies are only possible for selected patients and issues in an international context. The overarching goal is to include as many patients as possible in clinical trials (Phase I-III) in order to offer those affected innovative therapeutic approaches with the greatest possible patient safety on the one hand, and to gain the best possible insights for the development of new therapeutic options and standards on the other.
 

Scientific projects
In addition to the reference centre for nuclear medicine, we are conducting further scientific projects to research the mechanisms underlying the development of ACT and PCC/PGL (EpiGenPAT), the molecular characterisation of ACT (MoPACT) and the minimally invasive determination of tumour burden in ACT (predict ACT), in collaboration with the Experimental Paediatric Oncology Working Group and the Chair of Personalised Tumour Medicine and Molecular Oncology, among others.
  

Team
Dr Antje Redlich, clinical study director, Magdeburg University
Children's Hospital Prof. Dr Michaela Kuhlen, scientific study director, Swabian Children's Cancer Centre Augsburg
Dr Marina Kunstreich, study physician, Swabian Children's Cancer Centre Augsburg
  

Funding
The MET registry is financially supported by the Children's Cancer Foundation. 

The Reference Centre for Nuclear Medicine and the scientific project "MoPACT" are funded by the Central German Children's Cancer Foundation. 

NCT WERA, CCC WERA, BZKF, KIONET and more – networked research for better care for children and adolescents with cancer. Funding puts the Swabian Children's Cancer Centre in the Champions League of research. 

In Germany, approximately 400,000 adults and up to 2,500 children and adolescents are diagnosed with cancer every year. The Joint Federal Committee (the leading body for financing in the hospital sector) requires children's cancer centres to treat as many patients as possible in research studies in order to give them access to the most modern forms of therapy. While this is mandatory and successful in over 90% of cases in paediatric and adolescent haematology and oncology due to the long-standing close networking of the centres, the percentage is significantly lower for adults.  

There is therefore a gap in the conduct of clinical trials in Germany. This deficit and the lack of an appropriate infrastructure has been recognised by German Cancer Aid, the Bavarian state and the federal government and is to be improved through various funding opportunities. The declared goal of German policy is to treat most patients with cancer in Germany at so-called CCCs (Comprehensive Cancer Centres). Each C stands for research, teaching or patient care. Due to this broad setup, German CCCs are playing an increasingly important role in defining quality and treatment standards and advancing modern cancer medicine. To this end, they work closely with partners in their respective regions to provide the best possible care to all patients, regardless of location. For example, the Swabian Paediatric Cancer Centre has been a member of the CCC WERA network (Würzburg, Erlangen, Regensburg, Augsburg) since 2021 and a member of KIONET for ten years. 

In Bavaria: Close cooperation in the fight against cancer
Scientific research is one of the most important pillars in the fight against cancer. Since 1964, the German Cancer Research Centre (DKFZ) has been a nationwide institution dedicated to cancer research. In order to further intensify these efforts and provide additional funding for cancer research, Bavarian Minister-President Markus Söder established the Bavarian Centre for Cancer Research (BZKF) in 2019, modelled on the DKFZ. This inter-university institution, comprising all six Bavarian university hospitals, aims to further improve tumour diagnosis and therapy. The Bavarian state is investing tens of millions of euros in this project. The Bavarian university hospitals and medical faculties are pooling their resources in an interdisciplinary manner within the BZKF, networking and operating joint structures across locations, which are primarily dedicated to cancer research within the framework of study groups. A special feature of the BZKF is the citizen hotline, which is the first point of contact for those affected and can also refer people in the respective region to appropriate care facilities. Under the slogan "Strengthening excellence, sharing knowledge", the six Bavarian university hospitals have been working closely together in the BZKF for three years.  

The BZKF supports a study group on children and adolescents with CNS tumours. The spokesperson for this study group is Professor Frühwald. In another BZKF project that has just been approved for funding, the special group of young adults (aged 15-25) with high-risk CNS tumours will be researched in greater depth.  

CCC WERA is a leading oncology centre
Also in 2022, funding was approved for the establishment of a network of the so-called CCC WERA Centre of Excellence. For decades, German Cancer Aid has been using donations to fund various CCCs as part of an excellence initiative; a new development here is the funding of CCC networks. Due to the lack of a research branch at Augsburg Hospital until the university hospital was founded, it was not possible to apply for a Cancer Aid Centre of Excellence until recently. Thanks to the enormous efforts of individual clinical researchers at Augsburg University Hospital (especially in the field of paediatric oncology, e.g. paediatric oncology researchers Prof. Dr. Kuhlen, Prof. Dr. Johann and Prof. Dr. Dr. Frühwald) in paediatric oncology), the Augsburg University Hospital and its Cancer Centre in the WERA network have been positioned in such a way that a successful application for a centre of excellence has been achieved. Only 15 centres of excellence or networks are funded throughout Germany, some of which are part of a network structure. The CCC funding focuses on the best possible care, cutting-edge research, top-level training for young professionals and national and international competitiveness.  

In 2021, the CCC WERA network applied for one of six nationwide centres within the framework of the NCT (National Centre for Tumour Diseases) in a call for proposals by the Federal Ministry of Education and Research (BMBF). This application process is now well advanced and the NCT WERA site – under the leadership of the University Hospital of Würzburg – has excellent prospects of receiving funding. A major focus of the WERA network in the NCT is the provision of care in rural areas. The University Hospital of Augsburg, with its catchment area of almost two million people, is ideally suited for this purpose. The primary mission of the NCT is to conduct internationally competitive and visible cutting-edge research in the clinical-translational field. One of the particular strengths of NCT WERA lies in clinical research.  

Swabian Children's Cancer Centre benefits from funding
Due to the complexity of cancer and its development, funding is never sufficient, especially in the field of paediatric haematology and oncology. Nevertheless, the funding provided to Augsburg University Hospital by various initiatives (NCT, CCC and BZKF) greatly helps us in our efforts to improve cancer research, treatment and ultimately cure. For the CCC Augsburg and, as a result, the Swabian Children's Cancer Centre, participation in these initiatives means far-reaching national and international visibility and an enormous gain in prestige.  

Due to the changing structures in our healthcare system, increasing centralisation and, as a result, professionalisation, it is an absolute stroke of luck for our Swabian Children's Cancer Centre that we are involved in all these funding programmes. This not only secures the existence of the Swabian Children's Cancer Centre with all its facilities for the care of seriously ill children and adolescents, but also provides a tangible opportunity to further expand our expertise and provide even more children and adolescents with cancer with a steadily increasing and higher level of care.  

Despite all the adverse circumstances in global politics, we here at Augsburg University Hospital are looking to the future with hope. While FCA has now been in the Bundesliga for many seasons, Augsburg University Hospital and thus also the Swabian Children's Cancer Centre made it into the Champions League in 2022!

Our research focuses on the following questions:

• How do tumours develop in children and adolescents? 
• How do the genome and epigenome influence the metastatic behaviour and aggressiveness of certain types of cancer in paediatrics? 

A methodological focus is on the investigation of primary tumour tissue using state-of-the-art technologies.  

In addition to proven methods such as methylation classification and RNA sequencing, we also use innovative approaches such as single-cell sequencing to examine the single-cell transcriptome. This technique not only enables the precise quantification of individual tumour components such as tumour-infiltrating immune cells and stromal cells, but also the identification of the tissue of origin of certain tumour types.
  Our research thus contributes to a better understanding of the development of tumour diseases as well as to improved risk classification and is therefore directly relevant to clinical decision-making.
Another focus is on the spatial analysis of tumour tissue, in which individual areas of the tumour are visualised in high resolution in order to be able to assign individual cell populations very precisely. 

In addition to our work on primary tissues, we also focus on in vitro techniques such as high-throughput compound screening and CRISPR-Cas9 technology, which are key areas of our experimental research.  

A thematic focus is on the characterisation of rhabdoid tumours (study director: Prof. Frühwald), adrenocortical and adrenal tumours (scientific study director: Prof. Kuhlen) and rare embryonic and sarcomatous brain tumours (study director: Dr. v. Zezschwitz, Berlin & Prof. Johann, Augsburg). 

Specific projects currently include: 

• Molecular stratification of extracranial rhabdoid tumours, molecular evolution of rhabdoid tumours in recurrence (collaboration with Prof. Frühwald, EU-RHAB)
• Establishment of a molecular-based risk classification for adrenocortical tumours (collaboration with Prof. Kuhlen, Paediatric Clinic & Prof. Claus, Internal Medicine 2 and Pathology) 
• The role of long non-coding RNAs in SMARCB1-deficient tumours (collaboration with Prof. Pichler, Internal Medicine 2) 
• Genetics of rare brain tumours (DICER1-mutated sarcomas)
   

Our work has been/is supported by: 

• Else Kröner Fresenius Foundation
• German Cancer Aid  
• German Research Foundation (DFG) 
• Augsburg Medical Faculty 
• Fight Kids Cancer Consortium 

Team:
Prof. Dr. Pascal Johann
Dr. Marlena Mucha
Victoria Fincke, MSc.
Felix Dorn (TA)
Dr. Dajana Lobbes (TA)
Cand.med. Maurice Lossner
Cand.med. Svenja Steinhauser
Cand.med. Rebekka Prim 

Enquiries regarding collaboration opportunities or dissertations should be addressed to: pascal.johann@uk-augsburg.de 

The CNS-InterREST GPOH study group, led by Dr Barbara v. Zeschwitz in Berlin and Prof. Pascal Johann in Augsburg, focuses on the highly heterogeneous group of extremely rare embryonic or sarcomatous brain tumours in children.

  Many of the tumour types examined do not have a uniform histopathological appearance, but are characterised by specific genetic or transcriptional aberrations that can only be detected using modern molecular characterisation methods.

These tumours include:

• ETMR (embryonal tumour with multilayered rosettes) 
• FOXR2-activated CNS neuroblastomas 
• HGNET-BCOR (BCOR-altered tumours) 
• MN1-altered astroblastomas 
• Intracranial sarcomas (among others) 

In this context, regular consultations take place in our tumour board (every Thursday at 12 noon).
Further information can be found here. 

We are happy to answer any clinical or scientific questions you may have (cns-interrest@charite.de or pascal.johann@uk-augsburg.de).