ICRF Research Investigates a Mutation That Impacts Diffuse Midline Glioma (DMG)

Diffuse Midline Glioma (DMG – also known as Diffuse Intrinsic Pontine Glioma (DIPG)) is a rare and devastating brain cancer in children, with a survival rate of only 12 to 18 months. Prof. Meshorer and his team are working with a protein found to contain a specific mutation in over 70% of DMG patients, with the potential to develop new and effective therapies. 

Tell us about your current research project

My lab is studying epigenetics, a field which deals with changes to the genome (the DNA and its organization within the cells) but not changes to the DNA sequence itself. It includes, most notably, chemical modifications to the DNA or to the structural proteins, namely histones, that organize the DNA in living cells, as well as the composition itself of the histones, which can be replaced by different histone variants. In our ICRF project, we are working on one of those histone variants, called H3.3, which was found to contain a specific mutation in over 70% of Diffuse Midline Glioma (also known as Diffuse Intrinsic Pontine Glioma (DIPG)) cases, a rare and devastating brain cancer in children. In a model system of this cancer which we developed in embryonic stem cells, we characterized the immediate changes that occur once the mutation gets expressed inside the cells. 

“The unexpected is the most exciting thing about science. You never really know what to expect, and every discovery leads to a new direction.”

Dr. Meshorer

What excites you most about your research?

The unexpected is the most exciting thing about science. You never really know what to expect, and every discovery leads to a new direction. In this project for example, we generated stem cells which express the mutated form of the histone variant, H3.3. This mutation was known to lead to the inhibition of a specific enzyme, and it was assumed that this is the cause of the disease. As a control, we generated another mutation in the exact same location in the H3.3 gene, but which does not inhibit the enzyme. We found that many of the changes we observed are shared by both mutations, suggesting that at least some of the cancer related phenotypes are not directly due to the inhibition of the enzymatic activity. 

Where do you hope this will lead?

These cancers are incurable and deadly with a life expectancy of 1-1.5 years. Current therapeutic directions concentrate on the inhibition of this enzymatic activity, but I hope that our study will open new directions for combined therapies (such as enzymatic inhibitors together with drugs that target stem cells), because it is now clear that not all changes can be ascribed to the inhibition of the enzymatic activity. 

What has receiving an ICRF grant meant to you and your career?

ICRF actually funded one of our earlier projects, more than 12 years ago, and enabled us to work on reprogramming mature cells to “pluripotent” stem cells (‘pluri’-‘potent’ refers to their potential to generate all cell types), a field which are still currently pursuing, so it was extremely important for my lab, my career, and the trajectory that we ended up following. The current project is also not the main focus on my lab, so the ICRF grant strengthened and enabled this direction, and ensures our continued efforts on cancer epigenetics.