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An embryonic stem cell activated FOXM1 transcriptional program marks ultra-high-risk primary neuroblastoma patients for FDI-6 small molecule inhibition

Boekbijdrage - Boekabstract Conferentiebijdrage

Introduction: Chemotherapy resistance is responsible for high mortality rates in high-risk neuroblastoma patients. MYCN is a major oncogenic driver in these tumors controlling pluripotency genes including LIN28B. Therefore, we hypothesized that enhanced embryonic stem cell (ESC) gene regulatory programs could mark tumors with increased risk for therapy failure enabling the selection of patients for novel targeted therapies. M&M: A microRNA expression ESC-signature was established based on publically available data. In addition, an mRNA ESC-signature of top 500 protein coding genes with highest positive correlation with the microRNA ESC-signature score was generated. Results: High ESC-signature scores were significantly correlated with worse neuroblastoma patient survival, both in the global patient cohort as well as in the subset of stage 4 tumors without MYCN-amplification. In addition, both in neuroblastoma and other embryonal tumors exhibiting MYCN-activation, the scores were significantly higher. This was confirmed in MYCN cell model systems where the scores altered upon MYCN-overexpression/knock-down. Using GSEA, we identified that genes implicated in DNA damage response and cell cycle control were strongly enriched in the signature. One of the genes in the signature is the transcription factor FOXM1, which is a master regulator driving those pathways. The upstream activator of FOXM1, MELK, was also part of the signature. Inhibition of FOXM1 in neuroblastoma cells using the small molecule FDI-6 significantly reduced cell viability. In addition, MELK inhibitors are currently tested in vitro and both FOXM1 and MELK inhibitors are evaluated in MYCN transgenic zebrafish models. Conclusion: A novel ESC-signature score marks neuroblastomas with poor prognosis enabling the identification of ultra-high-risk neuroblastoma patients that may benefit from targeted therapies using FOXM1 or MELK inhibitors.
Boek: Combined SIOPEN annual general meeting and 4th Neuroblastoma Research symposium, Abstracts
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