Neuroblastoma Genomics

Ferroptosis is a form of cell death triggered when a lethal amount of free radicals accumulates within the cell. This occurs when the metabolic systems that regulate the balance of oxygen, iron, amino acids, and polyunsaturated fatty acids fail. Neuroblastoma cells are particularly vulnerable to ferroptosis due to their high metabolic activity. However, cancer cells have developed specific mechanisms to protect themselves from cell death by ferroptosis. The goal of our work is to understand the complex regulatory system in neuroblastoma cells and, by doing so, identify potential targets to selectively trigger ferroptosis and develop new therapeutic concepts. It is also crucial to understand how the regulatory systems differ across the various molecular subtypes of neuroblastoma, leading to different sensitivities to these therapies. Our research on ferroptosis is funded by the German Research Foundation (DFG) as part of the priority program SPP 2306, titled "Ferroptosis: From Molecular Foundations to Clinical Applications."

An important goal of our work for many years has been to identify target molecules in neuroblastoma cells that depend on high activity of the MYC(N) oncogene, since MYC(N) itself cannot easily be therapeutically targeted. Based on a siRNA screen, we identified the inhibition of the CDK12/13/CCNK complex as a potential target. In a drug screening, we identified various chemical substances that specifically target the CDK12/13/CCNK complex. These substances are based on a very similar chemical structure but have different modes of action. Some substances act as classical kinase inhibitors, while others function as so-called molecular glue degraders. These molecules exploit the cell's ubiquitin-proteasome system to selectively degrade their target proteins, thereby rendering them ineffective. Our work is supported within the framework of the international PROTECT project, which is part of the "Cancer Grand Challenges" program. The developed substances are clinically very promising and are being thoroughly tested preclinically for efficacy and safety.

Our group is part of the international project ITCC pediatric cancer data portal, which is an international partnership involving clinical programs spanning seven nations aiming to aggregate and harmonize genomic data from over 6000 pediatric cancer cases. 

For more information see the project website: https://www.pedcanportal.eu/