The European "Fight Kids Cancer" (FKC) program has selected two projects involving researchers from the Research Institute Children's Cancer Center Hamburg for its 2024 funding round. They will receive funding of approximately 3 million euros. The research projects focus on childhood cancers that are particularly difficult to treat.
One of the grants will support the SOUP research project (Scanning the liquids of pediatric brain tumor patients to personalize treatment). The goal of the project is to develop a reliable, minimally invasive molecular test for brain tumors in children and adolescents that can be used to accurately assess the cancer independently of surgery. The international research team, which includes 14 centers in seven countries, is analyzing genetic material fragments from cerebrospinal fluid. The project is funded by the FKC with 1,998,000 euros.
"My research group has been working for a long time on the diagnosis of brain tumors using cerebrospinal fluid. Now we have succeeded in detecting and analyzing the tiniest amounts of free DNA," says Prof. Ulrich Schüller, head of the Developmental Neurobiology and Pediatric Neurooncology research group at the Research Institute "Kinderkrebs-Zentrum Hamburg". The decisive step forward was achieved by so-called nanopore sequencing. This method was used to detect characteristic tumor signatures in cell-free DNA from patients' cerebrospinal fluid (CSF). The DNA comes from dead tumor cells in the brain. When they die, their genetic material, the DNA, is released into the cerebrospinal fluid.
The second grant is for the EUROPE project (Exploring unknown relapse origins in pediatric ependymoma). It focuses on the third most common type of malignant brain tumor in children, ependymomas. In the event of a relapse, the chances of survival for affected children have been poor. David Ghasemi is the scientific coordinator of the project. He is a physician at the University Medical Center Hamburg-Eppendorf and a scientist at the Research Institute "Kinderkrebs-Zentrum Hamburg" in the Schüller research group as well as at the "Hopp Children's Tumor Center Heidelberg" (KiTZ). Within the framework of EUROPE, studies of tumor material will reveal the cellular mechanisms involved in relapse and identify new vulnerabilities in tumor biology. "We are convinced that the development of new, effective drugs against ependymoma can only succeed if we really understand the biological basis of this complex tumor type. With EUROPE, we want to make a decisive contribution to this," says David Ghasemi. EUROPE is funded with 878,000 euros and involves four centers in Germany and the Netherlands.
Managing Director Wiebke Cramer emphasizes the importance of funding in the context of national and international research cooperation: "The number of childhood cancers is very low. At the same time, they are the patients who lose the most years of life or must live the longest with the late effects of treatment. That is why support for pediatric cancer research is so important. We are pleased to be able to advance research in close collaboration with other research institutions."
"Fight Kids Cancer" is a European program supported by non-profit organizations dedicated to fighting childhood cancer and supporting affected families. It supports transnational early clinical trials and clinical research projects that have the potential to make a lasting difference for children with cancer. Five fundraising organizations have joined forces: Imagine for Margo (France), KickCancer (Belgium), Fondatioun Kriibskrank Kanner (Luxembourg), CRIS (Spain) and Kika (the Netherlands) receive donations from charity events such as charity runs.
Scientific contact
Prof. Ulrich Schüller
Research Institute "Kinderkrebs-Zentrum Hamburg
Email: schueller@kinderkrebs-forschung.de
Press Contact
Research Institute "Kinderkrebs-Zentrum Hamburg
Building N 63
Martinistr. 52
20251 Hamburg, Germany
Email: presse@kinderkrebs-forschung.de
About the Research Institute Children's Cancer Center Hamburg
The Research Institute Children's Cancer Center Hamburg was founded in 2006 by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg e.V. with donations. At the institute, a multidisciplinary team of around 50 clinically active doctors, scientists, technical assistants, and dedicated employees investigate the molecular mechanisms of cancer development in children in order to develop new approaches for better and more targeted therapies. Donations, sponsorships, and private commitment make the research work possible. The institute is supported by a scientific advisory board and works closely with the University Medical Center Hamburg-Eppendorf (UKE) and the Leibnitz Institute of Virology (LIV). Cooperation with national and international research institutions as well as with clinical patient care at the UKE creates optimal conditions for the successful treatment of children with cancer. Around half of the project costs are covered by competitive third-party funding - including from the German Research Foundation, German Cancer Aid, the Federal Ministry of Education and Research, and the European Union.
About childhood cancer
In Germany, around 2,200 children and adolescents are diagnosed with cancer every year - the most common forms are blood cancers (leukemias), brain tumors, and tumors of the lymphatic tissue. In contrast, carcinomas, which account for more than 90 percent of new cases in adults, are rare. Being diagnosed with cancer is deeply upsetting for families and turns everyday life upside down. Treatment usually lasts for weeks and months. The various forms of therapy are extremely stressful for young patients. Acute side effects are highly likely to occur. Another cause for concern is the increasing number of serious late effects of radiotherapy and chemotherapy for childhood cancer. In general, thanks to successful research in recent decades, great success has been achieved in the fight against childhood cancers. Today, the diseases are curable in many cases: around 80 percent of all those affected survive. This is a great success when you consider that just a few decades ago, these children had hardly any chance of survival. Nevertheless, too many children still die of cancer today or experience a serious loss of quality of life as a result of the disease or the treatment methods.
They are rare and occur in both the brain and spinal cord of children: Tumors called ependymomas. Three scientists from Prof. Ulrich Schüller's research group at the Research Institute "Kinderkrebs-Zentrum Hamburg" have now achieved groundbreaking results that will make it possible to better diagnose and treat these tumors in the future.
Ependymomas account for almost five percent of all tumors of the central nervous system in children. The tumor cells arise from ependymal cells, which line the inner walls of the brain's ventricles and the spinal canal. Effective treatments are currently limited to complete surgical removal of the tumor and radiation therapy. In young children in particular, efforts are made to avoid irradiating the brain in order to avoid permanent damage. Knowledge to better classify these tumors and predict their evolution is essential to make treatment as gentle and effective as possible for each patient.
In the case of spinal ependymoma (SP-EPN), there is now more clarity. Dr. Sina Neyazi has studied these tumors, which occur in the spinal cord, and found that there are two subtypes that progress differently. Subtype A is more likely to recur, meaning the tumor will come back, while subtype B is unlikely to recur. The two subtypes differ at the molecular level. Among other things, certain changes in the genetic material, known as NF2 mutations, occur in the more severe subtype A, while these mutations are not found in subtype B, or only rarely.
Prof. Schüller explains how these new findings translate into clinical practice: "Nobody dies from these spinal cord tumors. But what do I tell the parents after the tumor has been surgically removed? Should they come back in six months, a year, or two years to have their child examined? Or should they assume that the tumor has progressed so well that they only need to come back if symptoms recur?”
With Dr. Neyazi's results, it is now possible to classify the course of the disease much more clearly by molecular analysis of the tumor tissue. Detailed insights into the molecular properties of these tumors are also essential for the development of new treatment strategies.
In her work, Lara Pohl examined 2,023 ependymoma data sets. In doing so, she created a data set that provides reliable information on how certain molecular characteristics affect the progression of the tumor and the survival rate.
The last comparable analysis was performed in 2015, but it included only 500 samples, which meant that some tumor classes were still missing. Pohl was now able to fill in the missing data, verify the findings from that study, and investigate differences between the different subtypes of ependymoma. "Our data are particularly relevant for rare and poorly understood tumor subtypes and apparently benign variants that have higher recurrence rates than previously thought," says Prof. Schüller. The study also revealed new insights into individual tumor subclasses, such as the fact that certain ependymomas, previously thought to occur only in the cerebrum, also occur in the cerebellum.
The raw data from this comprehensive ependymoma analysis is available in full on the Internet for other scientists to download. This has created a valuable resource for further research.
Pohl and her colleagues have also developed a machine-learning model that can be used to predict how the tumor will progress based on certain molecular characteristics of a tumor sample, called the methylation profile. This could lead to the development of a more direct and personalized diagnostic tool for clinical practice.
Posterior fossa ependymoma type A (PF-EPN-A, PFA) often has a poor outcome, with more than half of patients not surviving the disease. They usually occur in young children between the ages of two and five. Swenja Gödicke, like Lara Pohl also a medical student at the University Medical Center Hamburg-Eppendorf (UKE), discovered that the cell density within a tumor differs in these ependymomas. A high cell density is associated with a worse course of the tumor.
The differences between areas of high and low cell density in the tumor tissue sections, which are already visible under the microscope, are reflected at the molecular level. For example, chromosomal abnormalities characteristic of this tumor, which indicate a poor prognosis, were more common in cell-dense areas. Tissue samples from relapses, i.e. recurrences of PF-EPN-A, also showed an increased number of cell-dense areas.
The results of Swenja Gödicke show for the first time how important it is for the assessment of this brain tumor to determine the number of cell-dense areas and to perform molecular analyses of these areas.
"With these three studies, we have made valuable new contributions to the classification of ependymomas. They are also the result of many years of reference pathology work in which we receive ependymomas from all over Germany for evaluation in Hamburg," says Prof. Schüller.
Original publications
Neyazi, S., Yamazawa, E., Hack, K. et al. Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation. Acta Neuropathol 147, 22 (2024). https://doi.org/10.1007/s00401-023-02668-9
Pohl, L.C., Leitheiser, M., Obrecht, D. et al. Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas. Acta Neuropathol 147, 24 (2024). https://doi.org/10.1007/s00401-023-02674-x
Gödicke, S., Kresbach, C., Ehlert, M. et al. Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology. Acta Neuropathol 147, 23 (2024). https://doi.org/10.1007/s00401-023-02682-x
Scientific contact
Prof. Ulrich Schüller
Research Institute Children's Cancer Center Hamburg
Email: schueller@kinderkrebs-forschung.de
Press contact
Research Institute Children's Cancer Center Hamburg
Building N 63
Martinistr. 52
20251 Hamburg
Email: presse@kinderkrebs-forschung.de
About the Research Institute Children's Cancer Center Hamburg
The Research Institute Children's Cancer Center Hamburg was founded in 2006 by the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg e.V. with donations. At the institute, a multidisciplinary team of around 50 clinically active doctors, scientists, technical assistants, and dedicated employees investigate the molecular mechanisms of cancer development in children in order to develop new approaches for better and more targeted therapies. Donations, sponsorships, and private commitment make the research work possible. The institute is supported by a scientific advisory board and works closely with the University Medical Center Hamburg-Eppendorf (UKE) and the Leibnitz Institute of Virology (LIV). Cooperation with national and international research institutions as well as with clinical patient care at the UKE creates optimal conditions for the successful treatment of children with cancer. Around half of the project costs are covered by competitive third-party funding - including from the German Research Foundation, German Cancer Aid, the Federal Ministry of Education and Research, and the European Union.
About childhood cancer
In Germany, around 2,200 children and adolescents are diagnosed with cancer every year - the most common forms are blood cancers (leukemias), brain tumors, and tumors of the lymphatic tissue. In contrast, carcinomas, which account for more than 90 percent of new cases in adults, are rare. Being diagnosed with cancer is deeply upsetting for families and turns everyday life upside down. Treatment usually lasts for weeks and months. The various forms of therapy are extremely stressful for young patients. Acute side effects are highly likely to occur. Another cause for concern is the increasing number of serious late effects of radiotherapy and chemotherapy for childhood cancer. In general, thanks to successful research in recent decades, great success has been achieved in the fight against childhood cancers. Today, the diseases are curable in many cases: around 80 percent of all those affected survive. This is a great success when you consider that just a few decades ago, these children had hardly any chance of survival. Nevertheless, too many children still die of cancer today or experience a serious loss of quality of life as a result of the disease or the treatment methods.
Medulloblastoma is the most common malignant brain tumor in children. Treating a medulloblastoma requires very intensive multimodal therapy, which includes surgical resection, intensive chemotherapy and, in some cases, radiotherapy. This therapy is very stressful for the children, has numerous side effects and also often leads to serious negative effects on neurocognitive development long after the therapy. Dr. Catena Kresbach from Prof. Dr. Ulrich Schüller's research group has been working intensively with other scientists over the last 4 years on researching an innovative therapeutic approach for medulloblastoma treatment. In a mouse model for childhood medulloblastomas, they investigated the effect of a molecule called vismodegib, which specifically inhibits a signaling pathway that is overactivated in the subgroup of so-called sonic hedgehog medulloblastomas. It is known from previous studies that vismodegib administered orally (as a tablet) achieves very good results in terms of tumor reduction, but causes serious bone side effects in children. Dr. Kresbach and her colleagues were able to show in their recent publication that injecting vismodegib into the cerebrospinal fluid (so-called intraventricular therapy) leads to a significant reduction in the tumor burden. At the same time, intraventricular administration prevented the therapy from having a negative effect on bone growth. Since such intraventricular therapy for children with medulloblastoma is already routinely carried out in the clinic for the chemotherapeutic agent methotrexate, Dr. Kresbach's work forms a valuable basis for treating vismodegib as a future therapy for medulloblastoma in children. The work was recently published in the journal Neuro-Oncology.
Scientific exchange in the field of pediatric oncology
With the bridging seminar financed by the Stoll VITA Foundation, we bring clinicians and scientists together and enable professional exchange with internal and external experts.
We are looking forward to the next bridge seminar on August 20 at 4:30 p.m. with Dr. med. Dr. rer. nat. Roland Imle from the DKFZ/Child Tumor Center Heidelberg, who will talk about his current research work in the field of pediatric brain tumors. The host of this event: Prof. Dr. Ulrich Schüller.
REFERENT: Dr. med. Dr. rer. nat. Roland Imle, DKFZ / Children's Tumor Center Heidelberg
LECTURE: "Somatic muscle engineering for flexible in vivo modeling of childhood sarcoma"
DATE: September 20, 2023, 4:30 p.m.
LOCATION: Children's UKE, Lecture Hall O47 (Orthopedics)
Brain tumors are one of the major challenges in pediatric oncology. They are characterized by an enormous biological heterogeneity and are at the top of cancer-related mortality rates in children due to their often aggressive course. Professor Dr. Ulrich Schüller and his team from the Research Institute Children's Cancer Center Hamburg, in close collaboration with other research groups, including the University Medical Center Hamburg-Eppendorf (UKE) and the University Medical Center Schleswig Holstein (UKSH), have succeeded in bringing a new diagnostic method into clinical use that could soon substantially improve the care of patients with brain tumors. The study results are now published in the journal Clinical Chemistry (Oxford University Press).
Liquid biopsy enables precise molecular tumor classification
The gamechanger is a technique called nanopore sequencing - a safe and gentle method that detects tumor signatures on cell-free DNA (cfDNA) from the patient's cerebrospinal fluid (CSF). It detects tumor-specific changes in copy number profiles and epigenetic changes in DNA, which - after comparison with large databases - enable precise molecular classification. Whereas complex and risky neurosurgical interventions such as tissue biopsies or resections were previously necessary, with this method, researchers only need a few milliliters of brain/spinal fluid. "Thanks to the CSF biopsy method, we can make a reliable diagnosis - without any stressful intervention for the child," explains Prof. Dr. Ulrich Schüller, also referring to patients with inoperable tumors for whom even a tissue biopsy is associated with a particularly high risk, e.g. those with tumors of the brain stem. Here, the novel cerebrospinal fluid analysis provides diagnostic certainty. "In the case of tumors that must and can be operated on, the preoperative diagnostic method also enables us to plan surgical interventions more individually and align them with the tumor entity," adds Ulrich Schüller.
Since the new method also provides evidence of residual disease or relapse, Ulrich Schüller and his colleagues are optimistic that nanopore sequencing of cfDNA from cerebrospinal fluid samples will also be an important component for monitoring children with a brain tumor in the future. Conceivably, chemotherapies and radiation could be resumed as soon as a relapse is detected via the cerebrospinal fluid - and not only when clinical symptoms or evidence is found in imaging. The technology will be implemented in clinical trials in the medium term to randomize patients based on molecular results of CSF diagnostics. Results of the study data, which includes 129 CSF samples from a total of 99 patients, can be read here
Data cast their shadows ahead. Research awards in advance of publication
The relevance of the data is demonstrated by no less than three research prizes awarded to the scientists of the Research Institute Children's Cancer Center Hamburg in the run-up to publication. For example, Professor Schüller received the 2023 Science Award from the German Society for CSF Diagnostics and Clinical Neurochemistry (DGLN). In addition, Ann-Kristin Afflerbach from the Schüller research group was awarded the Young Investigators Bronze Award at the 13th ISMRC (International Symposium on Minimal Residual Cancer). In addition, the doctoral student recently received the coveted Hubertus Wald Young Investigator Award from the University Cancer Center Hamburg (UCCH).
Original publication
The data are published in the current issue of the journal Clinical Chemistry. Click here to access the publication
New approaches in the diagnosis of childhood brain tumors: Nanopore Sequencing
Prof. Dr. Ulrich Schüller is a senior physician at the Institute of Neuropathology, responsible for the diagnosis of pediatric brain tumors and for molecular neuropathology. The focus of his research at the Research Institute Children's Cancer Center Hamburg is the neurobiology of pediatric brain tumors and pediatric neuro-oncology.
"Pediatric brain tumors are characterized by a large biological heterogeneity and lead the way in cancer-related mortality in children. Many tumors are highly aggressive; we can observe how quickly cells divide or infiltrate the brain. The idea of children suffering from such tumors, of such tumors changing the lives of children and entire families from one day to the next, and of children sometimes suffering the consequences of therapy for the rest of their lives, is terrible and brings with it a great responsibility. We as scientists see ourselves as having this responsibility to better understand such tumors and, as a consequence, to identify or develop substances that slow down tumor growth."__Prof. Dr. Ulrich Schüller.
In 2023, the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg e.V., together with the Clinic for Pediatric Hematology and Oncology (PHO), will continue to offer four grants (1000 EUR / month each) for medical students, who are interested in a dissertation in the field of pediatric cancer research (1 year / full-time / start: October 1, 2023). Current topics in pediatric hematology and oncology are: leukaemia, non Hodgkin lymphoma, immunotherapy, brain tumors, stem cell transplantation, coagulation, late effects
Procedures and deadline
If you are interested, please send your application with CV, letter of motivation, certificates (iMed certificate / physics / Abitur) as a single PDF file by May 31. 2023 to Astrid Evert (buero@kinderkrebs-forschung.de, Tel: 040 / 42605- 1210).
Selection committee: Prof. M. Horstmann, Prof. I. Müller, Prof. S. Rutkowski, Prof. U. Schüller.
Translational support of young scientists
Support of young medical scientists is central focus of our research institute. The institute is integrated into an excellent research network through cooperation agreements with the Hamburg University Medical Center Hamburg-Eppendorf (UKE) and with the Leibniz Institute for Virology (LIV).
Our approach: Support experimental research and training of young scientists in the field of pediatric oncology.
The German Society for Gene Therapy (DG-GT) is an association of physicians, natural scientists and other professional groups who deal with questions of experimental and clinical gene therapy. Every quarter, the society awards high-ranking gene therapy publications with the DG-GT "Paper of the Quarter" price. In Q4/22, a current publication by PD Dr. rer. nat. Kerstin Cornils and Dr. rer. nat. Anna-Katharina Franke (AG Müller) was convincing, in which a novel therapeutic approach for cancer entities for which no antibody CAR has been available so far is presented. The researchers describe for the first time the functionality of a novel chimeric antigen receptor (CAR) based on the binding of C-type lectins to glycan structures. The novel LEC-CAR concept offers several advantages over normal antibody-based CARs: broader applicability, short generation time and low immunogenicity.
For 140 years, Germany's oldest medical award, the Dr. Erich Martini Price, has honoured significant medical research achievements. On Monday, Science Senator and Second Mayor of the Hanseatic City of Hamburg Katharina Fegebank and Prof. Dr. Ansgar W. Lohse, Chairman of the Dr. Martini Foundation Board and Director of the I. Medical Clinic and Polyclinic of the UKE, presented the awards to five UKE scientists. Dr. Michael Bockmayr, clinician-scientist in the research group of Professor Dr. Ulrich Schüller, received the second price for his risk evaluation of spinal cord tumours using bioinformatic methods.
Prognosis of ependymomas – Identifying patterns of recurrence
Myxopapillary ependymomas (MPE) are rare tumours of the spinal cord, whichoccur in all age groups. Until now, they were considered to be rather benign, but recurrences occur frequently, especially in younger patients. Dr. Michael Bockmayr was able to divide the tumours into two main subtypes - MPE-A and MPE-B - with molecular data profiling and bioinformatical methods. He found that 85 percent of patients with MPE-A tumours had a recurrence within ten years, while this was the case in only 33 percent of patients with MPE-B tumours. "These findings make it possible for the first time to robustly identify patients with an increased risk of recurrence, for which anappropriate follow-up care should be provided," explains Dr. Michael Bockmayr. "The results show that for certain tumours, concomitant radiation or chemotherapy could be useful. We hope that our results can helpto improve the treatment success in the long term through risk-adapted therapeutic decisions".
Foto: UKE/Kirchhof
New and innovative approaches for tomorrow's cancer research were the focus of Future X Change - an event of the National Decade against Cancer. The Research Institute Children's Cancer Centre Hamburg participated. Together with other supporters, topics such as the promotion of young researchers, participation and current BMBF research projects were discussed and thought about further. The event kicked off with an address by Federal Research Minister Bettina Stark-Watzinger.
As part of the Decade, we are committed to ensuring that the goals of the DGK are also achieved for paediatric oncology: For a childhood without cancer #knackdieletzten20
