Development of a ROS- and lysosome-addressing combination treatment for relapsed Neuroblastoma

High-risk Neuroblastoma (NB) patients often relapse. Mesenchymal (MES) NB are less differentiated and respond poorly to chemotherapy compared to Noradrenergic (ADR) NB. Cancer cells produce high levels of reactive oxygen species (ROS), which are involved in biological processes. At moderate levels, ROS are scavenged by antioxidants, whilst during oxidative stress cell death is promoted. Our previous data revealed a higher lysosomal content and indicated higher levels of some antioxidant-related genes in MES tumor cells. We hypothesize that more lysosomes are associated with ROS detoxification, rendering MES tumor cells chemo-resistant. Here, we aim to overcome resistance by identifying drug combinations of ROS inducers sensitizing MES NB cells, and unraveling the mechanism of interaction between lysosomes and ROS. The drug combinations will be validated ex vivo (INFORM registry-derived cultures) and in vivo (zebrafish embryo PDX models). We are currently establishing high-content imaging pipelines to study ROS and lipid peroxidation levels in multiple NB cell lines and patient-derived long-term cultures, established from fresh tissue samples, obtained through the INFORM program.

 

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Publication History

Article published online:
09 May 2025