# Modeling pediatric glioma in human ES cells:mechanistic and therapeutic insights

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $408,750

## Abstract

Abstract / Project Summary
 DIPGs are rapidly lethal brain tumors of childhood. The majority of patients die within a
year or two of diagnosis, as there is no effective treatment for this devastating disease. Their
critical location in the brainstem has long prohibited access to tumor tissue. Recently,
sequencing studies revealed novel histone mutations consisting of single amino acid
substitutions in the tail of the histone H3 variants. A pattern of exclusive co-occurrence of
histone mutations with specific signaling pathway alterations as well as age of onset and brain
region alterations emerged. Taking advantage of these data and of the strict developmental
window of the tumors, our team has built what is effectively the first genetically-engineered
human ES cell-based model of a tumor. The model yielded tumors that recapitulated the
genetic, transcriptomal, epigenetic and histological features of the disease, thus providing
valuable tools for the study of the disease. Genome wide studies suggested that the histone
mutation led to a resetting of the developmental status of the cells to an earlier more primitive
stem cell state.
 Importantly, our modeling system served as an effective platform for drug screens,
leading to the identification of a novel protein –protein interaction network as a key component
of the proliferative and growth machinery of these tumors, centered on the protein menin.
Menin is a unique protein with multiple partners; it is oncogenic in the context of the MLL
rearranged leukemias. Our data show that silencing menin or inhibiting its MLL interaction with a
menin inhibitor leads to a decrease in proliferation and increased cell death, a completely novel
finding never reported in glioma, that raises the promise of a therapeutic strategy.
 The proposal aims to expand our hES modeling platform by building new models that
are representative of the genetic diversity of the somatic mutations described in brainstem
gliomas. We will also study the events downstream of the histone mutations, with emphasis on
the molecular basis of the oncogenic role of menin. The ultimate goal is to develop a therapeutic
strategy for DIPGs, taking advantage of newly synthesized menin inhibitors.
 Our studies should also contribute to developing hES cells into a more widely applicable
platform for cancer modeling capitalizing on their many advantages, including access to an
unlimited supply of stage appropriate human cells for mechanistic or therapeutic studies, the
ability to study tumor biology from the step of initiation to tumor maintenance, and the ease of
implementing sophisticated genetic tools.

## Key facts

- **NIH application ID:** 9965800
- **Project number:** 5R01CA208405-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** VIVIANE TABAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965800

## Citation

> US National Institutes of Health, RePORTER application 9965800, Modeling pediatric glioma in human ES cells:mechanistic and therapeutic insights (5R01CA208405-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9965800. Licensed CC0.

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