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Targeting ferroptosis in cancer therapy

Award Number: R01CA269646
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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Targeting ferroptosis in cancer therapy - Project Summary Studying regulated cell death is critical for our understanding of tumor suppression and development of novel effective cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death that is induced by excessive lipid peroxidation, is morphologically and mechanistically distinct from other forms of regulated cell death such as apoptosis. However, in contrast to our deep understanding of apoptosis, how ferroptosis is regulated and coordinates with other cellular signaling in tumor suppression remains much less well understood. There also exists a significant need to translate our understanding of ferroptosis mechanisms into effective cancer therapies. Our long-term goal is to understand the mechanism(s) of action of anti-neoplastic agents and/or combinations of agents that target ferroptosis in cancer therapy. The objective of this application is to determine the role and mechanisms of AMP-activated protein kinase (AMPK), a critical sensor of cellular energy status, in regulating ferroptosis and the relevance of these regulatory functions to tumor suppression and treatment. Energy stress depletes ATP and induces cell death. Surprisingly, our recent study revealed that energy stress can potently suppress ferroptotic cell death through activating AMPK. Cancer cells with high basal AMPK activation are resistant to ferroptosis, and AMPK inactivation sensitizes such cancer cells to ferroptosis. Our recent publication and new preliminary data support the central hypothesis that AMPK inhibits ferroptosis through AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and biosynthesis of polyunsaturated fatty acid (PUFA) as well as other unidentified downstream effectors. AMPK can have either tumor-suppressive or -promoting functions, depending on the context. We further hypothesize that AMPK’s tumor-promoting function is at least partly mediated by its inhibition of ferroptosis, and combining AMPK inhibitors and ferroptosis inducers (FINs) is a novel therapeutic strategy for treating AMPK-dependent cancers. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1: To study the mechanisms by which AMPK inhibits ferroptosis in cancer cells. Specific Aim 2: To determine the relevance of ferroptosis to AMPK-mediated tumor development and treatment. It is expected that our proposed studies will clarify how AMPK regulates PUFA biosynthesis, identify novel regulatory mechanisms of ferroptosis pathways, and reveal a previously unrecognized function of ferroptosis suppression in AMPK-mediated tumor promotion in cancer. Our proposal is highly innovative because it focuses on a previously unexplored pathway linking AMPK regulation of ferroptosis to tumor development. Our proposed studies will have significant impact on both our basic understanding of ferroptosis and our ability to target AMPK or ferroptosis in cancer treatment.


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 = $493,996 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$49,400
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	2/13/2025	NON-COMPETING CONTINUATION	$444,596
														Subtotal = $493,996

Issue Date FY: 2024 ( Subtotal = $469,297 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	4/17/2024	NON-COMPETING CONTINUATION	$24,701
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	2/12/2024	NON-COMPETING CONTINUATION	$444,596
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	1/3/2024	NEW	$0
														Subtotal = $469,297

Issue Date FY: 2023 ( Subtotal = $493,996 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	2/24/2023	NEW	$493,996
														Subtotal = $493,996

Grand Total All Awards = $1,457,289

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Targeting ferroptosis in cancer therapy

Award Number: R01CA269646

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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