Ultra-high-risk pediatric cancer - combinatorial drivers and therapeutic targets for precision medicine

Although cure rates of children, adolescents and adults with cancer have improved considerably through
research and therapy optimization studies, patients are frequently ill-served by conventional therapies, such
as combination chemotherapy, and often relapse and succumb to the disease. These patients are commonly
referred to as ultra-high-risk and require therapies that are focused on specific genetic or epi-genetic targets.
In our study we focus on childhood cancer, specifically neuroblastoma, as a model for overly aggressive
disease. Neuroblastoma is a tumor affecting the peripheral nervous system. It affects mainly young children
and despite intensive treatment, the chances to be cured are still below 50% in high-risk cases. The underlying
genetic and epigenetic alterations and cellular pathways responsible for the aggressive phenotype are not
well understood. Therefore, we investigated genetic mutations in neuroblastoma, specifically in the ATRX
gene, which is often found in patients with ultra-high-risk neuroblastoma. In addition, we studied ATRX’s role
in metastasis. Single cell sequencing allowed us to understand the exact molecules and cellular programs
active in tumor cells that metastasize to the bone marrow and how tumor cells and immune cells interact.
We found that tumor cells with ATRX mutations weaken the immune system by signalling to monocytes and
turning them into allies that further promote disease progression. Using CRISPR- and drug screens, we
identified new and more specific treatment approaches, which are promising to be tested in further preclinical and early clinical trials. Finally, we developed a zebrafish model for ATRX mutated neuroblastoma, the
first animal model for this type of neuroblastoma, by implanting ATRX mutated human tumor cells into
zebrafish larvae. The fish larvae carrying tumors were then tested for drug effectiveness. Fluorescently
labelled tumor cells in the transparent fish can be visualized in an automated microscopy platform that
measures their growth or shrinkage. This platform will be important to test novel drugs and may help
determine whether patients will respond to treatments in personalized precision medicine. The combination
of the knowledge gathered on relevant molecular pathways and personalized test models will provide
oncologists a solid basis for informed therapy decisions.