Post-doctoral Fellowship Grant Awarded to Andrew Groves

There has been a vast increase in our understanding of the biology of DIPG over the last decade; however, this has not yet been translated into any new treatments or improvement in patient outcomes. I am particularly interested in finding combination strategies that work by fighting DIPG from multiple angles in order to outsmart this aggressive cancer. I have found that combining two drugs, an HDAC inhibitor and an LSD1 degrader, is highly effective in killing DIPG cells. HDAC inhibitors are currently being studied in clinical trials for patients with DIPG, while degraders are a new class of drug compounds that work by binding to a protein of interest and “tagging” it for destruction by the cell’s normal recycling mechanism (the proteasome). The goal of this project is to thoroughly investigate the mechanism by which these drugs synergize, and determine whether this strategy is feasible for translation to clinical trials. In order to do this, I will use a multi-disciplinary approach to fully dissect the relationship between HDAC and LSD1 in cell culture models of DIPG.

I will also test a panel of HDAC inhibitors as well as the LSD1 degrader to see how well they penetrate through the blood-brain barrier (BBB), and whether the combination decreases tumor growth and prolongs survival in our mouse models of DIPG. Finally, I will work to synthesize new degraders that can target both HDAC and LSD1 for degradation using a single drug. The ultimate goal of this work is to yield a novel strategy poised for clinical translation in this devastating pediatric disease.