# Lipid metabolism as a therapeutic vulnerability in BET inhibitor-resistant medulloblastoma

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2021 · $65,994

## Abstract

Project Summary/Abstract
 MYC-driven medulloblastomas are a particularly devastating group of pediatric brain tumors that exhibit
resistance and continued progression despite standard of care treatments. Our preclinical work[1] identified
BET-bromodomain inhibitors as a potentially promising new class of drugs for children with medulloblastoma
(MB) and other MYC-driven cancers, providing rationale to evaluate these agents in clinical trials. However,
treatment with BET inhibitor (BETi) alone is unlikely to be sufficient for a cure, with most tumors evolving to
acquire resistance to single-agent targeted therapies. An attractive strategy to overcoming therapy resistance
is to identify and exploit new vulnerabilities that exist in drug-tolerant cells. Metabolic pathways are of particular
interest in this context as they often rely on few essential enzymes, are frequently “rewired” in cancer cells vs.
normal cells, support and drive adaptive resistance to drug, provide essential survival capabilities, and can be
easily targeted with pharmacologic inhibitors[3]. Our previous work applied an integrative genomics approach to
identify genes and pathways mediating BETi response in MB[2]. These studies revealed that MYC-driven MB
cells with acquired resistance to BETi reinstate transcription of essential genes suppressed by drug and exhibit
changes in cell-state and new vulnerabilities not present in drug-sensitive cells. We now have a growing body
of evidence showing that BET inhibition downregulates the expression of key lipid metabolism genes and
metabolism-related signaling pathways, and that MB cells with adaptive resistance to BETi differentially
express and exhibit preferential dependency on specific lipid metabolic genes and transcriptional regulators.
These findings led me to hypothesize that metabolic reprogramming creates novel vulnerabilities in BETi drug-
tolerant MB cells that can be targeted to overcome resistance. The studies described herein will characterize
the altered lipid metabolism of BETi-resistant MB cells, assess the impact of BETi-driven metabolic rewiring on
cell signaling and the resistance phenotype, and investigate the possibility of exploiting lipid metabolic
dependencies as a novel approach to overcome resistance to BETi-targeted therapy.

## Key facts

- **NIH application ID:** 10234303
- **Project number:** 1F32CA261034-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Leslie Lupien
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234303

## Citation

> US National Institutes of Health, RePORTER application 10234303, Lipid metabolism as a therapeutic vulnerability in BET inhibitor-resistant medulloblastoma (1F32CA261034-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10234303. Licensed CC0.

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