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Mechanisms Promoting Copper Dependent Cell Death in Cancer

Award Number: R01CA279550
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mechanisms Promoting Copper Dependent Cell Death in Cancer - PROJECT SUMMARY Copper is an essential co-factor for enzymes across the animal kingdom yet even modest intracellular concentrations can be toxic, resulting in cell death. The toxicity of copper prompted the development of copper ionophores such as elesclomol as potential cancer therapeutics. However, lack of clarity regarding their mechanism of action has prevented their clinical development despite a favorable tolerability profile in clinical trials. We have recently described that copper ionophores promote a surprising new form of regulated cell death, distinct from other known and well annotated cell death pathways (such as apoptosis, ferroptosis and necroptosis). This new form of regulated cell death is copper dependent (hence termed “cuproptosis”) and is regulated by mitochondrial FDX1 and cellular protein lipoylation, a conserved lysine post-translational modification regulating only 4 key mitochondrial enzymes. Despite this essential role in enabling cuproptosis, little is known about the natural function of FDX1 in the cell, and the regulation and manifestation of protein lipoylation in different cancer types. Establishing a coherent mechanism explaining FDX1 and protein lipoylation regulation of copper ionophore induced cell death is crucial for any future attempts to repurpose these molecules as cancer therapeutics. As such, we will combine multidisciplinary approaches that include genomic and proteomic perturbation strategies with metabolite profiling and multiplexed imaging in cell culture and distinct mouse tumor models to determine the natural function of the key regulators of cuproptosis (FDX1 and protein lipoylation) in cancer cell growth and tumor formation, enabling a mechanistic understanding of how they regulate cuproptosis. Specifically, in Aim 1, we will focus on elucidating the natural function of the key regulator of cuproptosis, FDX1, in cells. We will take a focused approach to determine if it regulates Fe-S cluster biosynthesis or protein lipoylation, we will use proteomic approaches to characterize its protein-protein interactions, and we will perform deep mutational scanning to map the structure-function interactions of FDX1. In Aim 2, we will specifically focus on the unique regulatory role of lipoylated DLAT in promoting cuproptosis. We will use different image-based approaches to define the biophysical properties of lip-DLAT aggregates and their protein composition identifying links to multiple other cellular features. In Aim 3 we will first explore the levels of protein lipoylation across hundreds of cancer cell lines and establish the cell state associated with high lipoylation cancer cells. Then, we will determine the manifestation and dependency on FDX1 and protein lipoylation in both classic xenograft tumor models and in models of metastatic tumors growing in different organs. Lastly, we will use these in vivo models to establish the efficacy and on-target engagement of copper ionophores in cancer cell models that are predicted to be highly sensitive to these compounds. Together, this proposal will advance our understanding of the role of FDX1 and protein lipoylation in cancer and how these key regulators promote cuproptosis in cells and 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 = $595,634 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	3	6/30/2025	NON-COMPETING CONTINUATION	$595,634
2025	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	2	11/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$444,739
2025	2023	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Biology Research	000	1	11/25/2024	NEW	-$444,739
														Subtotal = $595,634

Issue Date FY: 2024 ( Subtotal = $648,408 )
2024	2024	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Biology Research	002	1	6/21/2024	SUPPLEMENT FOR EXPANSION	-$31,002
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	003	2	6/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$648,408
2024	2024	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Biology Research	000	1	3/20/2024	SUPPLEMENT FOR EXPANSION	$31,002
2024	2023	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Biology Research	001	1	6/21/2024	NEW	$0
														Subtotal = $648,408

Issue Date FY: 2023 ( Subtotal = $590,188 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Biology Research	000	1	6/30/2023	NEW	$590,188
														Subtotal = $590,188

Grand Total All Awards = $1,834,230

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Mechanisms Promoting Copper Dependent Cell Death in Cancer

Award Number: R01CA279550

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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