# CDKN2A couples lipid metabolism to ferroptosis in glioblastoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $518,756

## Abstract

ABSTRACT
Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults; the median survival of
patients with GBM remains a dismal 14-16 months with no improvement over standard of care since its
introduction 15 years ago. Thus, identifying new therapeutic strategies for GBM is an urgent unmet medical
need. Significant evidence indicates that, similar to other cancers, GBM have reprogrammed metabolism to
support the requisite demands to fuel malignant growth and survival. Notably, work from our group and others
has demonstrated a link between specific genetic alterations (e.g., EGFR) in GBM and rewired metabolism,
consequently revealing nodes of therapeutic intervention to exploit GBM metabolism. However, comprehensive
molecular profiling has shown that there is considerable molecular heterogeneity among GBM patients, and an
unbiased investigation into how this molecular diversity in GBM shapes the metabolome has yet to be conducted.
In preliminary studies, we have used integrated next-generation sequencing (RNA and Exome Seq) together
with large-scale “shotgun” lipidomics from over 50 GBM patient and patient-derived samples to determine if
molecular heterogeneity influences the lipidome of GBM. Using this cutting edge, systems-level approach we
have identified a unique lipid signature enriched in GBM tumors with deletion of the tumor suppressor, CDKN2A:
the most frequently altered driver gene in GBM. Importantly, as an apparent consequence of this specific lipid
enrichment, CDKN2A null GBM demonstrate selective susceptibility to ferroptosis – a recently described form of
lipid-peroxidation dependent cell death. These exciting preliminary results have led to the following aims both to
determine the underlying mechanistic basis for these observations and to evaluate the therapeutic potential of
inducing ferroptosis in CDKN2A-deleted GBM mouse models. In Aim 1, stable isotope-labeled metabolic tracing
and metabolic flux analysis will be conducted to evaluate how the loss of CDKN2A elicits a shift in fatty acid
composition relative to CDKN2A WT GBM. Aim 2 investigates the molecular pathways underlying enhanced
sensitivity to ferroptosis in CDNK2A null GBM. Finally, Aim 3 will assess whether the exploitation of ferroptosis
can selectively inhibit growth of CDKN2A null patient-derived orthotopic GBM xenografts. Together, the proposed
studies will provide mechanistic insight into a previously unappreciated link between a common genetic alteration
in GBM (CDKN2A deletion) and composition of the GBM lipidome, and evaluate the therapeutic potential of
ferroptosis in controlling growth of this genetically-defined subset of GBM tumors.

## Key facts

- **NIH application ID:** 10377523
- **Project number:** 5R01NS121319-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** STEVEN J BENSINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $518,756
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377523

## Citation

> US National Institutes of Health, RePORTER application 10377523, CDKN2A couples lipid metabolism to ferroptosis in glioblastoma (5R01NS121319-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10377523. Licensed CC0.

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