Project
Research Grant Emmanuel Van de Schueren to Suzanne Vanhauwaert: BRIP1 and BIRC5 as novel therapeutic targets in neuroblastoma
Neuroblastoma (NB) is an aggressive neural crest derived childhood tumor with poor survival rates, especially in
older children. Thus far, three bona fide oncogenic driver genes have been identified in neuroblastoma: MYCN,
amplified in roughly half of all aggressive neuroblastoma cases, ALK mutations or amplifications in 10% of cases
and rare LlN28B amplifications. Chromosome 17q gain is by far the most common DNA copy number alteration
in NB but thus far the causal 17q driver genes remain to be identified due to the large size of the recurrently
involved chromosome segments. In this project, we took advantage of an in silico integrative approach to identify
new driver genes located on 17q. In a first step, we used the firmly established TH-MYCN neuroblastoma mouse
model to explore the early transcriptional changes in MYCN-driven tumor development. In a second step, we
applied the CONEXIC algorithm which integrates copy number variations, gene expression data and miRNA
data, on 221 NB primary patient samples. As such, we were able to identify two new driver genes on 17q with
great therapeutic potential, namely BRIP1 and BIRCS.
For BIRCS a zebrafish model was established and subsequently crossed with the well established dl3h-MYCN
zebrafish model. In this model acceleration of NB tumor development was observed, clearly pinpointing to a
cooperative role between BIRCS and MYCN in NB development. Further evaluation of the role of BIRCS in
neuroblastoma development will be investigated using the BIRCS zebrafish model as well as exploration of
BIRCS inhibitors.
While BIRCS is involved in apoptosis as firmly established hallmark of cancer, BRIP1 represent a completely
new type of target in cancer connected to upregulated DNA damage response, a novel counter intuitive cancer
hallmark. Extensive in vitro data have been performed in our laboratory and support an oncogenic role for BRIP1
in NB. Furthermore, in keeping with the role of BRIP1 in DNA damage response, elevated protein levels of
yH2AX and RPA32 were observed upon knock down of BRIP1 .
The support of the VLK finalizing grant will allow me to perform the final and crucial experiments for the BIRCS
and BRIP1 projects and write up two additional papers for my PhD thesis. The specific goals that I aim to
achieve are: 1) finish crucial and final experiments with regard to the role of BIRCS in NB development using the
available dl3h-BIRCS zebrafish; 2) expand BRIP1 in vivo data in relation to its presumed cooperative oncogenic
function and 3) finalization of my PhD thesis. Given the research experience I gained during this PhD thesis, the
already performed experiments and my research stay at Tom Looks lab (Dana Farber Cancer Institute and
Harvard Medical School, Boston, USA) where I initiated the BIRCS project and given the excellent expertise of
the host lab, I am confident that the proposed goals will be achieved within the period of one year.
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