Thursday, March 12, 2026 3/12/2026

MYCN drives a ferroptotic vulnerability in neuroblastoma

Award Number: R01CA276207
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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MYCN drives a ferroptotic vulnerability in neuroblastoma - Project Summary: Apoptosis is a type of programmed cell death and has for a long time been appreciated to be a hallmark of cancer cells. In recent years, drugs targeting the apoptotic pathway, such as the FDA- approved BCL-2 inhibitor, venetoclax, have revolutionized therapy in cancers which have a particular vulnerability to targeting this pathway. A different programmed cell death pathway, ferroptosis, has recently been discovered. Understanding which cancers may be vulnerable to the induction of ferroptosis and which targetable molecules are involved could lead to a new wave of successful cancer therapy. MYCN-amplified neuroblastoma (NB) is one of the deadliest subtypes of pediatric cancer. Here in, we demonstrate that amplified MYCN drives an aberrant iron capture program in NB and increases intracellular cysteine biosynthesis and selenocysteine dependence through multiple mechanisms to detoxify reactive oxygen species (ROS) accumulation as a result of high cellular iron. The consequence of these MYCN-directed changes is a synthetic lethality to genetic or pharmaceutical targeting of the glutathione/glutathione peroxidase 4 (GPX4) pathway resulting in ferroptotic cell death. This grant aims to expand our understanding of how MYCN alters cysteine and selenocysteine production and ferroptotic inducing pathways to sustain an antioxidant defense and how these pathways may be exploited pharmaceutically to improve therapeutic responses in this recalcitrant tumor type. Specific Aims: Aim 1: Characterize the ability of MYCN to suppress ferroptosis in neuroblastoma Aim 2: Identification of synthetic lethal ferroptosis resistance mechanisms in MYCN-amplified neuroblastoma Aim 3: In MYCN-amplified neuroblastoma mouse models, evaluate novel ferroptotic combination therapies Study Design: Using well characterized isogenic cell lines and patient-derived xenograft cell cultures, we will mobilize expertise in selenocysteine biosynthesis (Copeland), pantothenate kinase inhibitors (Rock), and genomic screening of ferroptotic pathway modifiers (Olzmann) to better define the ferroptotic vulnerability in MYCN-amplified NB and to uncover novel sensitizers to ferroptotic inducers in MYCN-amplified NB. The goal of these experiments is to not only better understand how the MYCN oncogene hijacks cysteine for selenocysteine production to mount a defense against an oxidized phenotype, but to create new therapeutics to create better anti-ferroptotic approaches in MYCN-amplified NB. To this end, we will work with our preclinical mouse model expert (Koblinski) and a NB clinical investigator (Glod) to build the preclinical evidence of synthetic lethal new therapies into the clinic for refractory NB patients.


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: 2026 ( Subtotal = $0 )
2026	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	3	1/30/2026	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $788,109 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	3	8/25/2025	NON-COMPETING CONTINUATION	$656,289
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	3	9/10/2025	SUPPLEMENT FOR EXPANSION	$131,820
														Subtotal = $788,109

Issue Date FY: 2024 ( Subtotal = $790,504 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	2	8/30/2024	NON-COMPETING CONTINUATION	$625,334
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	002	2	9/9/2024	SUPPLEMENT FOR EXPANSION	$125,229
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	001	1	9/3/2024	SUPPLEMENT FOR EXPANSION	$39,941
														Subtotal = $790,504

Issue Date FY: 2023 ( Subtotal = $696,725 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Treatment Research	000	1	8/30/2023	NEW	$696,725
														Subtotal = $696,725

Grand Total All Awards = $2,275,338

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MYCN drives a ferroptotic vulnerability in neuroblastoma

Award Number: R01CA276207

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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