Targeting the RAS pathway in high-risk neuroblastomas

Using exome sequencing data of primary high-risk neuroblastoma (NB) and NB cell lines, we have identified a panel of somatic mutations affecting the RAS-RAF-MEK-ERK pathway (hereafter referred to as RAS pathway), a core signaling cascade frequently activated in cancer. We hypothesize that the RAS pathway is activated in subgroups of high-risk NB, which may offer novel entry points for targeted therapies. In SP B2, we aim to determine the dependence of NB cell growth on this cancer-related pathway in vitro and in mouse xenograft models. For this purpose, we will determine the functional relevance of mutated RAS pathway genes and selected downstream targets in NB cell lines and in a neural crest progenitor cell line using gene silencing and/or ectopic overexpression. We will determine the antitumor effects of inhibitors targeting RAS pathway candidates alone and in rational combinations in vitro and in vivo. We will generate gene expression profiles from our experimental models, which will be used to identify gene signatures associated with RAS pathway activation, the clinical relevance of which will be evaluated in our comprehensive transcriptome databases of primary NB. Gene expression profiles will moreover be utilized to assemble more complex RAS-associated protein interaction networks to identify novel key molecules of NB tumorigenesis. We expect that our study will elucidate the significance of RAS signaling in NB pathogenesis, and determine its value for targeted interventions in high-risk NB patients.




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