# Modeling BRAF-fusion driven pediatric brain tumors in the mouse

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $624,546

## Abstract

PROJECT SUMMARY
Pilocytic astrocytomas (PAs) and disseminated diffuse leptomeningeal glioneuronal tumors (DLGTs) are two
types of brain cancer common among pediatric patients. PAs are low grade gliomas, generally presenting as
non-infiltrating tumor masses, but their anatomical location can have profound consequences, with symptoms
ranging from pressure headaches, cranial nerve defects, ataxia, loss of visual acuity, diabetes, and precocious
puberty. Surgery is the treatment of choice for these patients, although radical resection is not always possible,
In these cases, adjuvant radiation and/or chemotherapy is often administered with acute and long-term
toxicities that can be debilitating in young patients. In fact, although the majority of patients have a good
prognosis in terms of long-term survival following surgical resection, approximately 50% of patients suffer from
morbidity due to recurrence or therapy-related side effects, making PA a disease with an unmet need for better
therapeutic options. DLGTs, although less common than PAs, are even more challenging clinically due to
diffuse leptomenigial infiltration which precludes surgical intervention, leading to higher mortality rates
approaching 80%.
By far the most common genetic event—observed in nearly 70% of cases of both PA and DLTG—is a
recurrent tandem duplication on chromosome 7. As a consequence of this rearrangement, the N-terminal
portion of KIAA1549 becomes fused to the C-terminal portion of BRAF, which includes the kinase domain.
Loss of BRAF’s N-terminal regulatory domain in turn, results in constitutive dimerization and downstream
signaling in a RAS-independent manner. To generate an accurate mouse model of human cancer driven by
complex chromosomal rearrangements, our laboratory has recently developed a novel CRISPR-based
approach to induce specific chromosomal rearrangements in vitro and, more importantly, in vivo . The
CRISPR-Cas9 system is ideally suited for in vivo genome editing because it only requires co-expression of
Cas9 and an appropriately designed RNA molecule (sgRNA) to guide the bacterial endonuclease Cas9 to the
desired cut site. The method we have developed is based on the simultaneous expression of Cas9 and 2
sgRNAs designed to cleave at the desired breakpoints. As a proof of concept, we have demonstrated the
feasibility of this strategy by generating novel mouse models of EML4-ALK fusion driven lung
adenocarcinomas and BCAN-NTRK1 fusion-driven brain cancer. Encouraged by these successes, we propose
to use in vivo chromosomal engineering to model the KIAA1549:BRAF rearrangement in the mouse brain (Aim
1). We have already obtained a large body of preliminary data that demonstrate the feasibility of this approach.
Ex vivo generation of the KIAA1549:BRAF fusion in adult neural stem cells produces tumors upon orthotopic
injection that have characteristics of human DLTG. Efforts to faithfully recapitulate PA pathology will also be
explored using novel in vivo CRIS...

## Key facts

- **NIH application ID:** 10173717
- **Project number:** 5R01CA234129-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** ROBERT I BENEZRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $624,546
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173717

## Citation

> US National Institutes of Health, RePORTER application 10173717, Modeling BRAF-fusion driven pediatric brain tumors in the mouse (5R01CA234129-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10173717. Licensed CC0.

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