The role of BRCA1 as oncogenic replicative stress resistor in MYCN driven neuroblastoma

Sequencing of cancer genomes has generated a tremendous amount of new information that is
currently translated towards novel approaches for patient tailored (so called precision medicine)
treatment. In embryonal tumors such as neuroblastoma however, mutations are sparse thus
hampering such an approach. Interestingly, despite this relative lack of recurrent mutations,
specific patterns of chromosome copy number alterations (CNA) are very frequent in high risk
neuroblastoma cases. The host lab has set out a strategy to identify the genes located in these
chromosomal regions (in particular the most commonly affected chromosome 17q segment) that
are affected by dosage effects and could act as novel therapeutic targets. I obtained converging
evidence that BRCA1 is a novel 17q candidate dependency factor in neuroblastoma and
hypothesize that elevated BRCA1 protein levels contributes to a replication stress resistance
phenotype. To explore this, I will perform an in-depth characterization of the phenotypic and
transcriptional effects of modulated BRCA1 expression, identify key BRCA1 upstream regulators
that influence its expression and activity during neuroblastoma tumorigenesis and shed light on its
poorly explored role in control of replication-transcription conflicts. In addition, I will evaluate the
CDK12 inhibitor THZ531, affecting BRCA1 expression, as a novel entry point for synergistic drug
combinations in the context of neuroblastoma.