Monday, June 30, 2025 6/30/2025

Leveraging Vulnerabilities Induced by STING Activation in Pancreatic Cancer

Award Number: R01CA250529
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

Group Awards By:

View Award Description

Leveraging Vulnerabilities Induced by STING Activation in Pancreatic Cancer - PROJECT SUMMARY/ABSTRACT Stimulator of interferon genes (STING) is an emerging target for the treatment of solid tumors. Investigations of the therapeutic relevance of STING agonists have primarily focused on the immunomodulatory effects mediated by STING-activation dependent induction of type I interferons (IFN) in the tumor microenvironment. However, how IFN signaling induced by STING agonists impacts malignant cell signaling and metabolism is poorly understood and, whether these effects can be therapeutically exploited has not been investigated. Data are presented showing that STING is highly over-expressed in pancreatic ductal adenocarcinoma (PDAC) and that its activation in PDAC malignant cells results in impaired tumor growth in an IFN-signaling dependent manner. Thus, elucidating the consequences of STING-driven IFN signaling is particularly relevant in PDAC which is the third-leading cause of cancer-related mortality in the U.S. with an overall survival of less than one year. Preliminary metabolomic and proteomic analyses point to two major interconnected biochemical processes impacted by IFN signaling in PDAC cells: (i) nucleotide metabolism, which is evidenced by the depletion of deoxyribonucleotide triphosphate (dNTP) and nicotinamide adenine dinucleotide (NAD) pools; and (ii) activation of the DNA replication stress response signaling pathway mediated by Ataxia Telangiectasia and Rad3-related protein (ATR). This proposal is designed to test the hypothesis that STING-driven dNTP and NAD depletion in malignant cells result from the transcriptional upregulation of SAM domain and HD domain- containing protein 1 (SAMHD1), a powerful dNTP phosphohydrolase, and of specific members of the poly- ADP-ribose-polymerase (PARP) family (PARP9/10/14) which increase NAD consumption, respectively. It will further test the hypothesis that malignant cells engage specific adaptive mechanisms to counteract these metabolic alterations and that their inhibition will synergize with STING agonists. Studies in Aim 1 will investigate the consequences of STING activation in orthotopic PDAC cell line and patient-derived xenograft models from a pre-existing repository and will investigate mechanistic links between STING activation and replication stress. Studies in Aim 2 will test rationally designed combination therapies that block two major co- dependencies elicited by STING activation in PDAC cells: (i) the ATR-regulated replication stress response and (ii) nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide recycling. Studies in Aim 3 will employ immunocompetent implantation and autochthonous PDAC models to test the concept of targeting co-dependencies identified in Aims 1 and 2 in the context provided by ongoing clinical trials in which STING agonists are combined with immune checkpoint blockade. Collectively, studies proposed in this application are designed to increase the understanding of the interplay between STING signaling, nucleotide/NAD metabolism and replication stress response in PDAC with the ultimate goal of uncovering critical vulnerabilities to be exploited by new therapeutic approaches against this extremely aggressive and difficult to treat malignancy.


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 = $515,600 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	5	1/23/2025	NON-COMPETING CONTINUATION	$515,600
														Subtotal = $515,600

Issue Date FY: 2024 ( Subtotal = $575,892 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$30,309
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	4	1/18/2024	NON-COMPETING CONTINUATION	$545,583
														Subtotal = $575,892

Issue Date FY: 2023 ( Subtotal = $613,590 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	3	2/1/2023	NON-COMPETING CONTINUATION	$565,439
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	001	3	2/13/2023	SUPPLEMENT FOR EXPANSION	$48,151
														Subtotal = $613,590

Issue Date FY: 2022 ( Subtotal = $699,640 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	002	2	5/16/2022	SUPPLEMENT FOR EXPANSION	$96,857
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	2	1/11/2022	NON-COMPETING CONTINUATION	$553,578
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	001	2	5/5/2022	NON-COMPETING CONTINUATION	$49,205
														Subtotal = $699,640

Issue Date FY: 2021 ( Subtotal = $630,802 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	1	2/12/2021	NEW	$630,802
														Subtotal = $630,802

Grand Total All Awards = $3,035,524

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Leveraging Vulnerabilities Induced by STING Activation in Pancreatic Cancer

Award Number: R01CA250529

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer