ONTHETRRAC
ONTHETRRAC uncovered clinically relevant aspects of tumor heterogeneity in childhood neuroblastoma.
Funded project
ONTHETRRAC
Overcoming Neuroblastoma Tumour HETerogeneity, Resistance and RecurrAnCe
Overview
ONTHETRRAC uncovered new aspects of tumor heterogeneity in childhood neuroblastoma that are important for accurate diagnosis, prognosis and overcoming treatment resistance.
This collaborative transnational project was led by Drs. Inge and Peter Ambros and Dr. Sabine Taschner-Mandl at CCRI, St. Anna Children’s Cancer Research Institute, Vienna, with partners from Charité Berlin, Institut Curie in Paris, Ghent University and the German Cancer Research Center in Heidelberg. It provided insights into tumor cells and molecular markers in solid and liquid biopsies and produced clinical diagnostic tools and recommendations now implemented in the new European high-risk neuroblastoma trial protocol.
Neuroblastoma remains a deadly disease for 60% of high-risk patients. Existing molecular classifiers and drug targets often derive from single biopsies of bulky tumors, but this simplified view is inappropriate. ONTHETRRAC assembled an international expert team in neuroblastoma molecular genetics and clinical research.
The team invested cutting-edge omics and liquid-biopsy technologies to overcome sampling inaccuracy and support analysis of clonal evolution, therapeutic targets and predictive biomarkers.
The research demonstrated genomic and proteomic heterogeneity between patients, within tumors and between tumor and relapse. Molecular markers and oncogenic drivers such as MYCN amplification, ALK alterations, telomerase activation and alternative lengthening of telomeres were found to have prognostic relevance.
ONTHETRRAC also provided recommendations for monitoring disease course at the subclonal level through circulating tumor DNA analysis, taking spatial and temporal heterogeneity into account. The resulting guidelines support targeted interventions, including ALK inhibitor treatment, and earlier relapse detection.
Interview
Meet Dr. Teresa Gerber, an early-career researcher involved in the ONTHETRRAC project.
Teresa Gerber carried out her PhD-related work at CCRI, St. Anna Children’s Cancer Research Institute, and successfully completed her PhD in 2020. She published a paper on blood sample handling conditions for liquid biopsy analyses.
How do you think this project has advanced our knowledge about the disease?
Liquid biopsies analyse molecular markers circulating in body fluids such as peripheral blood. DNA fragments released by tumor cells can provide genomic information and help track disease over time.
Our study provided blood-sample handling guidelines to harmonise pre-analytical processes and ensure high sample quality in multi-centre studies. I focused on how circulating genetic markers in blood and bone marrow change over time and compare with the primary tumor.
ONTHETRRAC showed that analysing one small diagnostic biopsy is insufficient because neuroblastoma is highly heterogeneous. We learned which markers and therapeutic targets diagnostic assays need to capture, and found that liquid biopsies can identify treatment-resistant subclones, track them and detect relapse earlier.
What has TRANSCAN-2 funding meant to you?
TRANSCAN funding enabled me to carry out my PhD at St. Anna Children’s Cancer Research Institute within a network of excellent European researchers. It also allowed me to attend consortium meetings and international conferences, including Advances in Neuroblastoma Research, where I presented my work. This supported both my training and my current career in clinical research.
How has the transnational collaborative aspect contributed to project success?
Pediatric cancers affect more than 100,000 patients a year in Europe, yet individual types are rare or ultra-rare. Transnational collaboration makes it possible to collect enough samples for statistically meaningful conclusions, including on subclonal mutations, and to establish harmonised European standards.
It also enables efficient exchange of highly specialised expertise, which is essential for high-quality research.
