Abstract 5416: Positioning the NQO1-bioactivatable drug isobutyl-deoxynyboquinone in diffuse intrinsic pontine glioma (DIPG): an exceptional therapeutic opportunity in pediatric brain tumor

2020 ◽  
Author(s):  
Maxime Henri Janin ◽  
Vanessa Ortiz Barahona ◽  
Pere Llinas Arias ◽  
Carolina De La Torre ◽  
Angel Montero Carcaboso ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Therapeutic Opportunity ◽  
Pediatric Brain

scholarly journals IMMU-09. OUTCOME OF PATIENTS WITH RECURRENT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH PEMBROLIZUMAB (ANTI-PD-1): A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i100-i100 ◽  
Author(s):  
Eugene Hwang ◽  
Arzu Onar ◽  
Tina Young-Poussaint ◽  
Duane Mitchell ◽  
Lindsay Kilburn ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Pediatric Brain

scholarly journals Diffuse intrinsic pontine glioma: current insights and future directions

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dilakshan Srikanthan ◽  
Michael S. Taccone ◽  
Randy Van Ommeren ◽  
Joji Ishida ◽  
Stacey L. Krumholtz ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Gene Mutations ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Current Standard ◽  
In Vivo Models ◽  
Landscape Models

AbstractDiffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor–related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

scholarly journals The H3K36me2 writer-reader dependency in H3K27M-DIPG

2021 ◽  
Vol 7 (29) ◽  
pp. eabg7444
Author(s):  
Jia-Ray Yu ◽  
Gary LeRoy ◽  
Devin Bready ◽  
Joshua D. Frenster ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Cellular Proliferation ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Chemically Modified ◽  
Functional Pathway ◽  
Pediatric Brain ◽  
Global Inhibition

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.

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