Decoding and targeting treatment-resistant metastatic neuroblastoma

The childhood cancer neuroblastoma (NB) is a major challenge in pediatric oncology, and children with relapse have a very poor prognosis due to treatment resistance at metastatic sites. We recently developed advanced patient-derived and humanized NB in vivo models and 3D tumor organoid models.

Here, we aim to develop and exploit these models, investigate mechanisms of NB metastatic treatment resistance, and target relapsed NB with cell state-directed combination therapies.First, we will develop patient-derived in vivo and ex vivo models of relapsed NB in the human metastatic bone marrow niche exposed to standard-of-care chemotherapy treatment.

These models will be exploited to investigate mechanisms of metastasis and treatment escape upon therapy and at relapse.

We will integrate NB and stromal cell lineages at single cell level, cell states, and molecular details with drug response and metastasis, and elucidate NB tumor cell plasticity and clonal evolution.

The mechanistic data will help us to identify novel cell state-directed therapeutic targets and compounds targeting relapsing and resistant NB. We will further exploit ferroptosis and targeted protein degradation to target relapsed NB.

Novel treatment strategies will be validated using 3D organoids and patient-derived in vivo models.The project will lead to a deeper understanding of NB metastatic treatment resistance and identification of novel cell state-directed treatments to target resistant and metastatic disease.