# Targeting Hexosamine Synthesis in Pediatric Brain Tumors

> **NIH NS R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2026 · $442,090

## Abstract

PROJECT SUMMARY
Pediatric brain tumors display differential mutational profiles and tumor biology than adult tumors, suggesting
that pediatric brain tumor patients are not simply small adults. Diffuse midline gliomas (DMG) often harbor a
specific lysine-to-methionine mutation in Histone 3 (H3K27a), which portend a 5-year survival rate of only 2%.
As a result, DMG-H3K27a tumors lose the histone regulatory marker, H3K27me3, leading to dysregulation of
the epigenetic landscape. DMG-H3K27a gliomas have unique metabolic needs, required to sustain their
epigenome and growth. We recently identified that DMG-H3K27a gliomas are dependent on the glycolytic
enzyme, Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3). PFKFB3 is a bifunctional protein
that catalyzes the synthesis or degradation of fructose-2,6-bisphosphate (F2,6BP) and is master regulators of
glycolysis. While the discovery and targeting of PFKFB3 and F2,6BP results in reduced growth, resistant
ultimately develops. Leveraging unbiased approaches we identified that resistance to PFKFB3 and glycolysis is
mediated by the Hexosamine biosynthetic pathway. We hypothesize that targeting this pathway as a single agent
or in combination with glycolysis inhibitors or novel codon optimized bacterial metabolic enzymes, reverses
resistance and selectively targets DMG cells compared to normal neural precursor cells and glial cells. These
efforts seek out to support that DMG-H3K27a tumors have additional selective and clinically targetable
dependencies. In the proposed studies we will investigate how these metabolic pathways support growth,
promote resistance to apoptosis and radiation. These studies are focused on laying the foundation for preclinical
therapeutic strategies.

## Key facts

- **NIH application ID:** 11330380
- **Project number:** 5R01NS138440-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sameer  Agnihotri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $442,090
- **Award type:** 5
- **Project period:** 2025-05-15T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11330380

## Citation

> US National Institutes of Health, RePORTER application 11330380, Targeting Hexosamine Synthesis in Pediatric Brain Tumors (5R01NS138440-02). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11330380. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*