Deciphering and targeting treatment resistant metastatic neuroblastoma

The successful management of children with treatment-resistant metastatic neuroblastoma (NB) remains a serious clinical challenge.

The overall objectives of this proposal are to understand NB treatment resistance and relapse in depth and to discover effective treatments for drug-resistant and metastatic NB.In aim 1, we will model and decipher NB treatment resistance.

Chemotherapy-treated NB PDX models will be analyzed by SNP array, single-cell DNA-sequencing, and RNA-sequencing to examine mechanisms of drug resistance and identify novel therapeutic targets.In aim 2, we will investigate mechanisms of NB metastasis and treatment response in the human bone marrow niche.

We will establish, characterize and utilize a novel human NB – human bone marrow in vivo model.

Mechanisms of NB metastasis and treatment response in the human bone marrow niche will be analysed using spatially resolved transcriptional profiling at single cell level.In aim 3, we will identify and test novel combination treatment strategies.

We will use 3D tumor organoids, high-throughput drug screening, artificial intelligence, combination synergy scores and orthotopic PDX models to identify and test novel anti-NB drug combinations.Our ambition is to increase the mechanistic understanding of NB treatment resistance and relapse, and to identify novel therapeutic regimens to treat high-risk NB.