Pdtm-28. Targeted Inhibition of Ezh2 and Bet Bromodomain Proteins for the Treatment of Diffuse Intrinsic Pontine Gliomas
Year: 2017
Type: conference-abstract
Abstract: Recent discovery of somatic histone gene mutations, resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3.3 proteins, in diffuse intrinsic pontine glioma (DIPG) has dramatically improved our understanding of disease pathogenesis, and stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. K27M mutant DIPG shows a dramatic reduction in global methylation at K27 residues on all 16 H3 proteins. This reduction in H3K27 methylation is believed to modify cellular gene expression in a way that favors tumor development. We have shown that inhibition of the H3K27 demethylase JMJD3 acts to restore K27 methylation in DIPG cells, while demonstrating potent anti-tumor activity, in vitro and in vivo. In addition to H3K27 methylation, H3K27 can also be acetylated (K27ac), which requires bromo- and extra-terminal domain (BET) protein activity. We have recently identified H3K27M-K27ac nucleosomes co-localize with BET bromodomain proteins at actively transcribed genes, whereas a polycomb repressive complex 2 (PRC2) is excluded from these regions, demonstrating that H3K27M and PRC2 occupy distinct chromatin regions in DIPG cells. Despite a major loss of H3K27 methylation, PRC2 activity is still detected in H3K27M DIPG cells, and the residual PRC2 activity is required to maintain DIPG proliferative potential by repressing neuronal differentiation and function. Small molecule inhibitor of EZH2 inhibited cell growth through the upregulation of gene that are normally repressed by PRC2 in DIPG. We also tested the anti-tumor activity of BET bromodomain containing protein 4 (BRD4) inhibitor, JQ1, and EZH2 inhibitor, GSK126, in our human DIPG xenograft model, and JQ1 and GSK126 treatment results in a significant delay of tumor progression and prolonged animal survival. Our findings suggest EZH2 inhibition could be a potential combinatorial strategy with BRD4 inhibition in treating K27M DIPG, that could counteract the development of resistance to single-agent epigenetic therapy.
Source: Neuro-Oncology
Institutions: Northwestern University, Lurie Children's Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767660282