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Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

Award Number: R01CA257148
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/09/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy - SUMMARY The overarching goal of this new R01 application is to investigate the dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer. This disruption of cellular metabolism, leads to the aberrant accumulation of reactive oxygen species (ROS), triggering maladaptive signaling that is an emerging, novel mechanism leading to ionizing radiation (IR) resistance (IRR) as well as enzalutamide (ENZ) resistance (ENZR). In this regard, recently identified a mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cellular metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, LNCaP cells expressing a MnSOD K68-Ac mimic mutant (MnSODK68Q) exhibited IRR/ENZR, increased HIF2�, known to promote stemness properties, and two stem cell markers, Oct4 and SOX2. As such, we seek to show that MnSOD-K68-Ac may drive IRR and/or ENZR, by altering MnSOD’s structural composition and enzymatic activity, and in a broader context, tumor growth and survival via a cell stemness-like mechanism. Finally, willGC4419 exposure, a chemical agent that acts as a MnSOD mimic, reverse the IRR/ENZR phenotype? Thus, it is It is hypothesized that prostate tumor cells exposed to IRR and/or ENZR increase MnSOD-K68-Ac, disrupting normal MnSOD biology at the cellular and mitochondrial level (i.e., aberrant ROS), which initiates cellular reprogramming, via increased HIF2�, leading to lineage plasticity properties, a change in tumor cell fate, and an IRR and/or ENZR tumor phenotype. It is also proposed that MnSOD-K68-Ac is a novel axis for new therapeutic interventions in IRR and IRR/ENZR tumors. Finally, through exposure to GC4419 that chemically replaces MnSOD activity, we ask whether superoxide detoxification reverts/converts these IRR/ENZR prostate tumor cells to a sensitive phenotype by restoring normal metabolism.


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	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	5	9/18/2026	NON-COMPETING CONTINUATION	-$252,603
2026	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	002	6	9/18/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,603
2026	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	5	3/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $383,789 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$38,378
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	5	3/21/2025	NON-COMPETING CONTINUATION	$345,411
														Subtotal = $383,789

Issue Date FY: 2024 ( Subtotal = $364,601 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	4	2/22/2024	NON-COMPETING CONTINUATION	$345,411
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$19,190
														Subtotal = $364,601

Issue Date FY: 2023 ( Subtotal = $444,242 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	3	3/8/2023	SUPPLEMENT FOR EXPANSION	$68,128
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	3	3/7/2023	NON-COMPETING CONTINUATION	$376,114
														Subtotal = $444,242

Issue Date FY: 2022 ( Subtotal = $445,632 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	002	2	4/28/2022	NON-COMPETING CONTINUATION	$30,704
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	2	4/1/2022	SUPPLEMENT FOR EXPANSION	$69,518
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	2	1/10/2022	NON-COMPETING CONTINUATION	$345,410
														Subtotal = $445,632

Issue Date FY: 2021 ( Subtotal = $382,941 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	1	4/9/2021	NEW	$382,941
														Subtotal = $382,941

Grand Total All Awards = $2,021,205

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Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

Award Number: R01CA257148

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/09/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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