Wednesday, September 17, 2025 9/17/2025

CDKN2A couples lipid metabolism to ferroptosis in glioblastoma

Award Number: R01NS121319
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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CDKN2A couples lipid metabolism to ferroptosis in glioblastoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $464,096 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/17/2025	NON-COMPETING CONTINUATION	$464,096
														Subtotal = $464,096

Issue Date FY: 2024 ( Subtotal = $501,221 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/14/2024	NON-COMPETING CONTINUATION	$465,051
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$36,170
														Subtotal = $501,221

Issue Date FY: 2023 ( Subtotal = $517,754 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/2/2023	NON-COMPETING CONTINUATION	$517,754
														Subtotal = $517,754

Issue Date FY: 2022 ( Subtotal = $518,756 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$51,875
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/11/2022	NON-COMPETING CONTINUATION	$466,881
														Subtotal = $518,756

Issue Date FY: 2021 ( Subtotal = $533,806 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/24/2021	NEW	$533,806
														Subtotal = $533,806

Grand Total All Awards = $2,535,633

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CDKN2A couples lipid metabolism to ferroptosis in glioblastoma

Award Number: R01NS121319

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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