# Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma

> **NIH NIH R01** · WILLIAM BEAUMONT HOSPITAL RESEARCH INST · 2022 · $333,504

## Abstract

ABSTRACT
Glioblastoma (GBM) continues to be an invariably fatal malignancy with limited treatment options. Our
laboratory studies tumor metabolism and its potential to serve as a novel therapeutic target. Through a series
of investigations, our group has identified that the diverse tumor ecology implicit in this malignancy contributes
to considerable intratumoral metabolic heterogeneity and dynamic metabolic reprogramming, allowing GBM
cells to adapt and proliferate under diverse, microenvironmental stresses. Specifically, through integrative
cross-platform analyses coupling metabolomics with genomics in patient-derived tumors, we identified
enhanced fatty acid oxidization (FAO) as a metabolic node in GBM driven by a transcriptional program
designed to import and utilize fatty acids from the tumor microenvironment. This metabolic phenotype was
specific to the mesenchymal subtype in GBM and recapitulated in preclinical models. Functional analyses
uncovered specific roles these fatty acids play in gliomagenesis, which are dependent upon nutrient
availability. In a state of glucose deprivation, mesenchymal GBM cells utilize these exogenous fatty acids to
serve as a vital, alternate source of ATP, whereas in nutrient favorable conditions, the intermediary metabolism
of FAO acts as a metabolic cue to drive a transcriptional program supporting cellular proliferation and
mesenchymal differentiation. Accordingly, inhibiting FAO in standard, nutrient rich conditions led to decreased
proliferation, however, robust energetic stress and non-apoptotic cell death was observed in mesenchymal
GBM cells in the context of glucose deprivation. In this application, we propose to extend these promising
findings by defining molecular mechanisms governing enhanced FAO in GBM (Aim 1), delineating the multiple
roles FAO may play in gliomagenesis in the context of this tumor’s diverse tumor ecology (Aim 2), and evaluate
the translational potential for eliciting metabolic synthetic lethality in GBM through energetic stress (Aim 3).

## Key facts

- **NIH application ID:** 10303047
- **Project number:** 5R01NS110838-03
- **Recipient organization:** WILLIAM BEAUMONT HOSPITAL RESEARCH INST
- **Principal Investigator:** Prakash Chinnaiyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,504
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303047

## Citation

> US National Institutes of Health, RePORTER application 10303047, Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma (5R01NS110838-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10303047. Licensed CC0.

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