Jan Molenaar / Marlinde van den Boogaard
13. Targeting aberrant ATRX to identify new treatment options for Neuroblastoma
In the Molenaar group we aim to identify genomic and/or immunologic perturbations in neuroblastoma and relate that to potential therapeutic interventions. We combine state of the art molecular techniques as CRISPR screening, single cell sequencing, high throughput compound screening and organoid technology.
In neuroblastoma, ATRX alterations are found in about 10% of high-risk patients with a poor prognosis. In this study, we aim to identify and validate new treatment options for ATRX mutant neuroblastoma. In neuroblastoma there is a unique ATRX mutation spectrum with very high frequency of multi-exon deletions that create ATRX in-frame fusions (IFFs). We have shown that these IFFs are essential for NB and induce a different phenotype than ATRX knockouts. We hypothesize that it is essential to consider these differences when investigating compound sensitivity. Therefore, we will use our unique series of isogenic models with ATRX IFFs/knockouts and our cell lines and organoid with endogenous ATRX IFFs to identify effective therapeutic strategies. The work can include CRISPR synthetic lethality screens, compound library screens, and identification of PROTAC interventions. In addition, since EZH2 inhibitors were effective in neuroblastoma models with an endogenous ATRX IFF, we will use our models to identify effective combination strategies with EZH2 inhibitors. The most promising combinations will be validated in vivo in ATRX mutant models. Our results should guide the clinical development of EZH2 inhibitor combinations or other effective combinations for ATRX mutant neuroblastoma in a phase 1/2 trial.
Necessary skills for this position:
- Master’s degree in Medical Biology, Computational Biology, Life Sciences or related field
- Previous experience with both ‘dry’ lab (data analysis) and ‘wet’ lab (cell culture, molecular assays) is appreciated
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