Therapeutic targeting of oncogenic chromatin regulation in childhood glioma

We are excited to advertise this Edinburgh Doctoral College Scholarship for the Institute of Genetics and Cancer. 

Further details of the scheme and application process can be found at: https://www.ed.ac.uk/institute-genetics-cancer/igc-graduate-research-and-training/edinburgh-college-doctoral-scholarship-projects

Diffuse Midline Glioma (DMG) is an incurable childhood brain tumour caused by a characteristic mutation in a histone H3 gene (H3K27M). The histone H3 protein is a constituent of the chromatin fiber involved in the epigenetic regulation of our genome; with the H3K27M mutation causing DMG by disrupting these important regulatory processes. Excitingly, epigenetic mechanisms have proven amendable to drug targeting with an increasing number of new therapies in clinical trials for cancer and other diseases^1,2. We have been studying how epigenetic regulation is disrupted in DMG tumour cells to better understand disease biology and discover potential new therapeutic opportunities³. Using CRISPR/Cas9 functional genomics approaches we discovered that DMG tumour cells require a specific subclass of the repressive epigenetic regulatory complex known as canonical Polycomb Repressive Complex 1 (cPRC1) (Unpublished). Further mechanistic studies have uncovered that these cPRC1 complexes are responsible for the inappropriate epigenetic silencing of hundreds of neurodevelopmental genes in DMG cells. Importantly, genetic targeting of cPRC1 reactivates these genes and significantly impacts DMG tumour cell viability. These discoveries have laid the ground work to pursue efforts in drug discovery/development to identify small-molecules targeting cPRC1 complexes to disrupt these important disease mechanisms.

This project will combine biochemistry and chemical biology approaches to better understand these complexes; and systematically identify small-molecules targeting their function(s). Purified, endogenous and recombinant complexes will be analysed using in-depth proteomic approaches (mass spectrometry) to characterise both their composition and structure. Information that will be combined with high throughput chemical biology screening platforms (small-molecule libraries) to identify compounds capable of directly binding intact complexes. In parallel efforts, we will combine high-content morphometric fingerprinting assays to identify small-molecules mimicking the effects of genetically disrupting cPRC1 in DMG cells or synergising with cPRC1 loss to inform future combinatorial therapy. “Hits” from these screens will form the basis of future drug development efforts towards the creation of high-quality compounds for pre-clinical and clinical evaluation in DMG patients. Overall, the goal of this project is to translate our growing understanding of DMG disease biology towards the development and implementation of much needed therapeutic approaches.