Ferroptosis induction as a novel treatment concept for relapsed childhood cancers

• Applicant: Privatdozent Dr. Frank Westermann
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology ; Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549939692

Neuroblastoma, arising in undifferentiated progenitor cells of the sympathetic nervous system in early childhood, is characterized by clinical and biological heterogeneity. Clinical courses range from spontaneous regression and differentiation to relentless progression despite intensive multimodal therapies. Amplified MYCN, TERT rearrangement and ATRX mutations, predominantly found mutually exclusive, are linked to more aggressive subtypes and are used to classify the patient at diagnosis as high-risk. We have previously identified that a subset of MYCN-amplified neuroblastoma cells is strongly addicted to cystine and highly sensitive to ferroptosis inducers (FINs), which is partly due to reduced cysteine/glutathione levels in MYCN-amplified cells. We have extensively characterized the interplay of the MYCN oncoprotein and the cysteine-glutathione-GPX4 system in different neuroblastoma subtypes. However, prediction of ferroptosis sensitivity using activity of MYCN and the cysteine-glutathione-GPX4 system is error prone, indicating that further mechanisms might be involved. Our preliminary data suggest that high activity of the GCH1-BH4-DHFR and the FSP1-CoQ axes strongly protect neuroblastoma cells from lipid peroxidation and ferroptosis. We will systematically analyse how the different systems cooperate and explore if combinatory targeting could lead to robust ferroptosis induction in preclinical neuroblastoma models. Biomarkers predicting ferroptosis sensitivity in neuroblastoma will be defined and tested also in other childhood malignancies.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2306: Ferroptosis: from Molecular Basics to Clinical Applications