BRIP1 and FOXM1 controlling replication stress in the neuroblastoma tumor genome

Neuroblastoma is a tumor arising in the nervous system and almost exclusively exist in children younger than five. Unfortunately, half of these tumors are very aggressive and still extremely difficult to cure. In recent decades it has been shown that neuroblastoma tumors almost have no mutations, but instead a lot of copy number alterations occur. One of these copy numbers is gain of 17q which is correlated with poor patient outcome. In this research project, I will make use of zebrafish to further unravel the role of 17q gain in neuroblastoma. In a first step, I will investigate if BRIP1 functions to control replication stress in neuroblastoma tumors. Therefore, an inducible BRIP1 zebrafish model will be created that can switch on the BRIP1 gene upon addition of doxycycline in the fish water. This will help me to further understand if BRIP1 is important in the initiation of the tumor development or in maintaining the tumor genome. In a following step, I will study how BRIP1 actually acts at the DNA replication fork. In a third step, I will study if the DNA
damage response is driven by FOXM1. Hence, a zebrafish model that overexpresses FOXM1 will be created. Finally, several compounds that target FOXM1 or the DNA damage respons pathway will be tested for use in neuroblastoma