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Use of H3(K27M) – Driven Zebrafish Models to Identify Targetable Vulnerabilities in DIPG
The prognosis for children with DIPG has not changed in nearly 50 years. Children have little chance of survival because there are still no effective treatments for this devastating brain cancer. Recently it was found that a majority of DIPG samples have a change in their DNA, a mutation called H3K27M. This finding hasn't translated into new treatments as originally hoped, in part because we lack the needed models to study how H3K27M promotes critical aspects of DIPG progression, such as very early events in DIPG development and the acquisition of treatment resistance. To fill this gap in knowledge, we have developed zebrafish models of H3K27M-driven DIPG. Zebrafish and human K3K27M protein are 100% identical, meaning they will have similar function in both species. Zebrafish have benefits over human cell lines and mouse models because fluorescently-tagged DIPG cells can be easily visualized and studied in the brain of living zebrafish, from the earliest stages of DIPG growth onwards to the development of treatment resistance. Zebrafish are also an inexpensive animal model for rapid and large-scale drug screens to find new treatments that kill DIPG cells but leave the normal brain cells undisturbed. The goal of our project is therefore to use our new zebrafish H3K27M-driven DIPG model in combination with next-generation sequencing techniques to define how H3K27M mutation causes DIPG to form from healthy brain cells, and how it gives the DIPG cells the ability to survive radiation treatment. We will also use our zebrafish models to rapidly screen a 770 compound FDA-approved drug library to find drugs that can be repurposed to help make DIPG cells very sensitive to radiation treatment. In total, this research will establish a novel animal model of DIPG and identify mechanisms by which H3K27M promotes DIPG progression. We hope that these findings will lead to the development of new treatments for DIPG and finally improve the prognosis of DIPG patients.