Primary resistance to chemotherapy is a major challenge in treating brain tumors today. Finding novel and specific tumor dependencies is therefore essential for effective drug development and improving patient outcomes.
High-grade gliomas (HGG) are the most aggressive brain tumors in children and young adults. They are uniformly fatal despite multimodal treatment strategies combining surgery, radiation and chemotherapy. High-grade gliomas of the brainstem, termed diffuse intrinsic pontine glioma (DIPG), have an especially grim prognosis – median survival has not changed over the last few decades and is currently still less than 10 months after diagnosis.1 As a first breakthrough in the field, deep sequencing efforts in 2012 revealed unique and highly specific K27M mutations in histone 3.3 and 3.1 side chains in more than 90% of DIPG and midline glioma cases2-4, whereas G34R/V mutations were exclusively found in histone 3.3 of hemispheric high-grade gliomas in about 40% of cases. However, the potential therapeutic applications of this discovery have not yet been systematically studied.
I hypothesize that we can exploit these epigenetic mutations to develop new therapeutic approaches. Specifically, I hypothesize that (I) the abovementioned histone tail mutations generate an aberrant epigenetic landscape that renders DIPG and HGG cells hypersensitive to specific epigenetic perturbations, thus offering an opportunity to screen epigenetic regulators for identifying unique tumor vulnerabilities.
