# FUNCTIONAL DISSECTION OF THE K27M HISTONE MUTATION IN GLIOMAGENESIS

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $349,988

## Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or
efficacious therapies exist. Recently, novel mutations in ACVR1, a BMP pathway receptor,
were discovered that commonly co-occur with a K27M mutation in the gene encoding histone
H3.1 (H3.1 K27M) in DIPG patient samples. The overall objectives of this proposal are to
identify the mechanisms by which mutant ACVR1 and H3.1 K27M contribute to DIPG
pathogenesis and to uncover strategies to pharmacologically target these mutations or
downstream signaling molecules. Our central hypothesis is that mutant ACVR1 and H3.1 K27M
contribute to brainstem gliomagenesis by activating the Stat3 and Notch signaling pathways,
respectively. We plan to use novel genetically engineered mouse models representing primary
tumors growing in their native microenvironment to interrogate the effects of both mutant
ACVR1 and H3.1 K27M on gliomagenesis, proliferation, apoptosis, cell differentiation, self-
renewal, cell motility, and angiogenesis in vitro and in vivo. We will also use both genetic and
pharmacologic tools to determine the contributions of Stat3 and Notch to ACVR1-mediated
functions and to H3.1 K27M-mediated functions, respectively. Finally, we will test a panel of
ACVR1, Stat3, and Notch inhibitors in vitro and in vivo in both human and murine DIPG models.
Once it is understood how ACVR1 mutations and H3.1 K27M contribute to DIPG pathogenesis,
the relevant developmental pathways can be manipulated pharmacologically, resulting in new
and innovative therapeutic approaches that are based upon the basic biology inherent, and
specific, to DIPG. We anticipate these outcomes will have a positive impact by 1) laying the
foundation for future pre-clinical and clinical trials for DIPG, 2) characterizing the first genetically
engineered mouse models of DIPG driven by mutant ACVR1 and H3.1 K27M, and 3) advancing
our understanding of signaling pathway activities that are essential for DIPG growth.

## Key facts

- **NIH application ID:** 9880404
- **Project number:** 5R01CA197313-06
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Oren Josh Becher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,988
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880404

## Citation

> US National Institutes of Health, RePORTER application 9880404, FUNCTIONAL DISSECTION OF THE K27M HISTONE MUTATION IN GLIOMAGENESIS (5R01CA197313-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9880404. Licensed CC0.

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