Brain tumor driver genes and new treatments for MYCN protein stabilization

Time period: 2014-01-01 to 2018-12-31

Project leader: Fredrik Swartling

Funder: Ragnar Söderberg Foundation

Type of award: Project grant

Total fundning: 8 000 000 SEK

MYC proteins like MYC and MYCN are transcription factors that have important roles in both brain development and cancer. In fact, MYC proteins are involved in more than half of all types of human cancer including severe forms of glioblastoma and medulloblastoma, the most common brain tumors in adults and children, respectively. We have generated several clinically relevant animal models to study brain tumor development. In these models we will now define from which specific cell type these brain tumors develop. We next want to identify genes that collaborate with MYC proteins in tumor development. Here we will use retroviruses and retrotransposons that can mutate DNA which enables us to study collaborating events in brain tumor development. In fact, we have shown that MYCN needs to be stabilized in order to generate brain tumors. We have in our collaborations found mutations in an enzyme FBW7 in brain tumor patients. FBW7 controls MYCN stabilization and we are now studying how FBW7 loss contributes to tumor formation in our models but also its mechanism in tumor cells from patient samples that we study in culture. Finally we identified two new substances that targets either MYCN production or MYCN stabilization. The first drug targets MYCN by epigenetic regulation and the other is a tumor cell cycle specific CDK2 inhibitor that we found can decrease MYCN protein stabilization. Our hope is to target both adult and childhood brain tumors with these drugs used in combination.