# A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)

> **NIH NIH R00** · UNIVERSITY OF CHICAGO · 2024 · $248,999

## Abstract

Diffuse
characterized
histone
substitution
levels
and By profilying the epigenome
of H3K27M mutant DIPG patient cells I found that H3K27M co-localizes with H3K27
acetylation (H3K27ac). In accordance with previous biochemical data, heterotypic H3K27M-
K27ac nucleosomes co-localize with bromodomain proteins at actively transcribed genes,
whereas PRC2 is excluded from these regions, suggesting that PRC2 is not sequestered at sites of
incorporation of H3K27M. I also showed that the heterotypic nucleosomes H3K27M-K27ac co-
localize with bromodomain proteins in DIPG, importantly treatment with BET bromodomain
inhibitors in DIPG xenograft mouse models potently reduces tumor growth and extend animal
survival. During my mentored phase (K99) I'm planning to study the molecular details of the
formation of the heterotypic nucleosomes using in vitro biochemistry and molecular biology
assays and gather further insights in the pathogenic mechanisms of aberrant acetylation and
H3K27M deposition in DIPG. While transitioning toward the independent phase (R00) I'm
planning to improve the BET inhibitors therapeutic strategy by identifying mechanisms of
resistance and cooperative factors that can lead to an improved and durable therapy for children
affected by DIPG. Altogether my plan is to perform experiments that push forward our
knowledge of this incurable disease with the goal of finally having a standard-of-care option that
can offer a reliable and efficacious treatment for DIPG patients.
Intrinsic Glioma (DIP G) a highly aggressive pediatric brainstem tumor
by rapid and nearly uniform patient demise. A heterozygous point mutation of
H3 occurs in more than 80% of these tumors, and results in a lysine-to-methionine
(H3K27M). Expression of this histone mutant is accompanied by a reduction in the
of Polycomb Repressive Complex 2 (PRC2) mediated H3K27 trimethylation (H3K27me3)
this is hypothesized to be a driving event of DIPG oncogenesis.
Pontine is

## Key facts

- **NIH application ID:** 10906265
- **Project number:** 5R00CA234434-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Andrea Piunti
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906265

## Citation

> US National Institutes of Health, RePORTER application 10906265, A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG) (5R00CA234434-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906265. Licensed CC0.

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