Decoding and Targeting Treatment-Resistant Metastatic Neuroblastoma

Introduction

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. There is an urgent need to better understand NB treatment resistance to inform the design of novel therapeutic strategies. However, current models do not mimic relapsed human NB in its most common metastatic niches in the bone and bone marrow.

Model Development

We recently developed advanced patient-derived and humanized NB in vivo models and 3D tumor organoid models, which are excellent tools for preclinical drug testing. Here, we aim to further develop and exploit these models, investigate mechanisms of NB metastatic treatment resistance/relapse, and target relapsed NB with combination therapies.

Patient-Derived Models

1. 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.
2. These models will be exploited to investigate mechanisms of metastasis and treatment escape upon therapy and at relapse.

Integration of Data

We will integrate NB and stromal cell lineages, cell states, and molecular details with phenotype and drug response. This will help elucidate NB tumor cell plasticity and clonal evolution. The mechanistic data and our new models will help us to identify novel therapeutic targets and compounds targeting relapsing and resistant NB, which we will validate experimentally.

Project Outcomes

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.

Expertise

My combined background in clinical medicine/pathology, in vivo/ex vivo modeling, NB chemoresistance, and preclinical drug testing, coupled with the development and application of state-of-the-art advanced assays, will generate the next generation of patient-derived models, mechanistic insight, and novel treatment against relapsed NB.