DIPG-24. TARGETED INHIBITION OF JMJD3 AND BET BROMODOMAIN PROTEINS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Katagi, Hiroaki; Louis, Nundia; He, Xingyao; Loughlin, Kathryn; Zhang, Ali; Ozark, Patrick; Horbinski, Craig; Lulla, Rishi; Saratsis, Amanda; Goldman, Stewart; David James, C; Shilatifard, Ali; Hashizume, Rintaro
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i53
• Page End: i53
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.117
• Languages: English
• ISSNs: 1522-8517

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 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. We have shown that the JMJD3 demethylase inhibitor, GSKJ4, 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. Increase level of H3K27 acetylation and bromodomain proteins in K27M-containing nucleosomes suggests that inhibitor of BET bromodomain protein 4 (BRD4), JQ1, could be useful for the treatment of K27M DIPG. Our aim is to investigate the hypothesis that the combined GSKJ4 + JQ1 have greater anti-tumor activity in vitro and in vivo than either monotherapy and reduce the likelihood of drug resistance. The level of H3K27 methylation and acetylation in DIPG cells with treated GSKJ4 + JQ1 were studied by western blotting. GSKJ4 + JQ1 increase H3K27 methylation and reduce K27acetylation in DIPG cells. Analysis on cell number showed that combination treatment of GSKJ4 + JQ1 significantly increases growth inhibition, compared with either therapy alone. In vivo response to monotherapy and combination of GSKJ4 + JQ1 will be measured by bioluminescence imaging and animal survival studies in human DIPG xenograft model.