Post-doctoral Fellowship Grant Awarded to Joana Graca Marques

DIPG is characterized by a mutation in proteins that structurally support the DNA named histones. A direct consequence of this mutation is the increase of a chemical modification on non-mutant histones deposited by an enzyme named EP300. The histone mutation also prevents glioma cells from differentiating into mature and non-proliferative brain glia cells. I hypothesize that interfering with the activity of EP300 can revert the oncogenic function of the histone mutation, allow tumor cell differentiation and, consequently, prevent tumor progression. Indeed, our initial experiments suggest that these glioma cells require EP300 for survival. Now, this project aims to validate EP300 as a promising target for DIPG therapy. To do so, I will test a vast panel of drugs able to disrupt the activity of EP300 in DIPG cells to assess their capacity to reduce tumor cell viability. Promising drugs will be evaluated for their ability to reach the brain at therapeutic concentrations and then tested in mouse models for their efficacy in preventing tumor growth and improving survival. As single agent therapy is unlikely to result in complete tumor regression, I will test EP300 targeting agents in combination with drugs commonly used in the context of cancer treatment to identify drug combinations that potentiate the effect of EP300 inhibition. Finally, using genetic silencing technology, I will remove EP300 from glioma cells and evaluate for changes in gene expression, tumor cell proliferation and differentiation. I will also test whether EP300-depleted tumor cells can still form tumors in mice to evaluate the potential of EP300 as a therapeutic target. In conclusion, this work seeks to change the treatment paradigm of these pediatric malignancies by exploring EP300 as a new actionable therapeutic target. Importantly, preclinical testing of EP300 pharmacological agents and drug combinations will inform future clinical trials for these universally fatal tumors.