Identifying Epistatic Suppressors of Oncohistone in Pediatric High-Grade Gliomas
In the cell, DNA strands are bound to structural proteins called histones to form chromatin; this in turn, facilitates the packaging of the genetic material to fit into the nucleus. The expression of genetic material can be enhanced or repressed by modification of such histones. Previously, our lab identified a high prevalence of mutations in the histone H3 gene in lethal childhood brain cancer. One of the mutations replaces the 27th amino acid residue lysine with methionine (H3K27M) creating a mutant histone that drastically disrupts chromatin modifications, leading to abnormal gene expression and tumour formation along the midline of the brain. Such tumours are impossible to surgically remove, and conventional therapies universally fail; raising an urgent need to identify novel means of disease treatment. Some recent studies have shown that these cancer cells may be respond to drugs that disrupts chromatin modification, but since these are processes that maintain normal cells, they may be unsafe to use in patients.
Project Goal:
Our long-term goal is to identify relevant and safe therapeutic targets for the treatment of these childhood brain cancers. We think that these chromatin perturbations and the disease may be reversible by genetic deletion of specific enzymes that modify the chromatin. Using a fruit fly model, depletion of one such chromatin modifier is indeed able to suppress tumors and defects associated with the H3K27M mutation but showed limited toxicity in normal flies. Using gene-editing on cell lines established from pediatric brain tumours containing H3K27M, we will assess whether depletion of this enzyme can abolish the tumorigenic activity of the mutation. The results from this study could potentially result in highly specific therapeutic targets for this deadly form of cancer.
Project Update 2024:
Within the cell, the strands of DNA are bound to packaging proteins called histones. These histones are mutated in a deadly form of brain cancer that occurs specifically in young children and adolescent teens. Using a fruit fly model, we show that the disease caused by histone mutations can be eliminated by targeting a protein that binds to histones and “writes” a modification. We are now using cells taken directly from tumors to repeat this finding and are seeing encouraging initial results in that targeting this “writer” leads to slower cancer progression. In the last year, we have validated this in tumor from another patient, and we are trying to understand how loss of this protein leads to cancer cell death. We currently working to understand how we can use this method to help patients.
