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Characterizing and targeting PRMT5 in autophagy for cancer treatment

Award Number: R01CA266522
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 08/17/2025

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Characterizing and targeting PRMT5 in autophagy for cancer treatment - Abstract Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer death in American women. Triple negative breast cancer (TNBC) accounts for 15% to 20% of all BC cases and has the worst prognosis and overall survival. Although many targeted agents are ongoing clinical trials, none have significantly improved the survival in TNBC patients. Thus, the identification of novel targets and effective strategies, including combination therapies, are urgent needed for TNBC patients. PRMT5 is emerging as a potential therapeutic target. Several PRMT5 inhibitors have been developed and are currently being evaluated in clinical trials, including a phase II trial for early-stage BC. Compared to other BC subtypes, TNBC displays the strongest PRMT5 expression. High PRMT5 expression is positively correlated with poorer survival rate in TNBC patients. Despite its association with TNBC progression, PRMT5 regulation and the molecular mechanisms by which PRMT5 promotes TNBC remain elusive. Moreover, TNBC cell lines display differential sensitivity or resistance to PRMT5 inhibitors, but the mechanisms have yet to be defined. Our preliminary studies demonstrate that: (1) PRMT5 is ubiquitinated by E3 ubiquitin ligase TRAF6, which is important for its activation and TNBC cell proliferation; (2) PRMT5 suppresses autophagy induction and catalyzes ULK1 arginine methylation; and (3) autophagy inhibition sensitizes TNBC cells to PRMT5 inhibitor. Based on these preliminary findings, we propose three aims to test our central hypothesis that TRAF6, PRMT5, and ULK1 form a novel axis to regulate autophagy and TNBC progression, and combination of PRMT5 and autophagy inhibitors is a potential strategy to combat TNBC. To validate our hypothesis, we propose three Aims. In Aim 1, we will define the mechanism through which TRAF6 regulates PRMT5 activation. In Aim 2, we will define the molecular function of PRMT5 in autophagy regulation by methylating ULK1. In Aim 3, we will evaluate the synergistic effect of PRMT5 and autophagy inhibitors in TNBC. We believe that our proposed studies will not only substantially advance current understanding of regulatory mechanism and biological function of PRMT5, but also provide a rationale for combination of PRMT5 and autophagy inhibitors to treat TNBC.


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 MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	3	1/27/2026	NON-COMPETING CONTINUATION	-$345,412
2026	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	002	3	2/12/2026	NON-COMPETING CONTINUATION	$0
2026	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	4	1/27/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$345,412
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $345,413 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	001	3	5/23/2025	NON-COMPETING CONTINUATION	$34,542
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	3	4/11/2025	NON-COMPETING CONTINUATION	$310,871
														Subtotal = $345,413

Issue Date FY: 2024 ( Subtotal = $328,143 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	2	4/19/2024	NON-COMPETING CONTINUATION	$328,143
														Subtotal = $328,143

Issue Date FY: 2023 ( Subtotal = $345,413 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	1	3/23/2023	NEW	$345,413
														Subtotal = $345,413

Grand Total All Awards = $1,018,969

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Characterizing and targeting PRMT5 in autophagy for cancer treatment

Award Number: R01CA266522

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 08/17/2025

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