Monday, October 27, 2025 10/27/2025

MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies

Award Number: R01CA253678
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/09/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies - SUMMARY The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype. In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit increased ROS levels and a high risk of recurrence due to endocrine therapy, has been identified. We recently found a novel mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD), which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2α (known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell biomarkers), leading to oncogenicity and pan resistance phenotype (PanR) to agents commonly used in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumors to exhibit a lineage plasticity phenotype. Based on our new data, our recent publication (Zhu et al, Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology, due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial metabolism. This initiates metabolic reprogramming, via increased levels of HIF2α, leading to a cell stemness-mediated tumor-permissive and/or PanR phenotype. Thus, we seek to further explore how MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to oncogenicity and/or PanR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic, reverse the oncogenic and/or PanR phenotypes?


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 = $469,637 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	003	5	9/19/2025	SUPPLEMENT FOR EXPANSION	$10,147
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	5	6/27/2025	NON-COMPETING CONTINUATION	$36,815
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	5	12/20/2024	SUPPLEMENT FOR EXPANSION	$91,328
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	5	12/19/2024	NON-COMPETING CONTINUATION	$331,347
														Subtotal = $469,637

Issue Date FY: 2024 ( Subtotal = $494,356 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	4	11/20/2023	NON-COMPETING CONTINUATION	$331,347
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	003	4	4/16/2024	SUPPLEMENT FOR EXPANSION	$7,610
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	4	4/16/2024	NON-COMPETING CONTINUATION	$18,408
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	4	11/30/2023	SUPPLEMENT FOR EXPANSION	$136,991
														Subtotal = $494,356

Issue Date FY: 2023 ( Subtotal = $411,535 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	3	3/14/2023	NON-COMPETING CONTINUATION	$29,452
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	3	8/11/2023	SUPPLEMENT FOR EXPANSION	$50,736
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	3	12/26/2022	NON-COMPETING CONTINUATION	$331,347
														Subtotal = $411,535

Issue Date FY: 2022 ( Subtotal = $360,799 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	2	4/28/2022	NON-COMPETING CONTINUATION	$29,453
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	2	12/15/2021	NON-COMPETING CONTINUATION	$331,346
														Subtotal = $360,799

Issue Date FY: 2021 ( Subtotal = $366,683 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	1	1/8/2021	NEW	$366,683
														Subtotal = $366,683

Grand Total All Awards = $2,103,010

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MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies

Award Number: R01CA253678

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/09/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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