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Investigating the roles of extracellular cGAMP and harnessing it for cancer treatment

Award Number: R01CA258427
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Investigating the roles of extracellular cGAMP and harnessing it for cancer treatment - PROJECT SUMMARY The goal of cancer immunotherapy is to awaken the body’s anti-tumoral immune response to fight against all cancers in all patients. Our lab recently identified a key mechanism by which cancer cells are detected by our innate immune system. We now know that cancer cells, with intrinsic chromosomal instability, constantly secret the soluble small molecule 2’3’-cyclic-GMP-AMP (cGAMP). Acting as an immunotransmitter, extracellular cGAMP is taken up by surrounding tissues and immune cells to activate its receptor STING in a paracrine fashion, resulting in downstream anti-cancer immune responses. The importance of extracellular cGAMP is demonstrated by our finding that it is required for the curative effect of ionizing radiation in a murine model of breast cancer. Furthermore, we identified the extracellular enzyme ENPP1 as the only detectable hydrolase of extracellular cGAMP that blocks its signaling pathway. Therefore, we hypothesize that ENPP1 is an innate immune checkpoint that could be targeted to expand the reach of cancer immunotherapy. Although ENPP1 is cGAMP’s only hydrolase, it hydrolyzes extracellular ATP at comparable potency. Therefore, genetic and pharmacological tools that are based on complete ablation of ENPP1 activity cannot be used to distinguish the physiological role between extracellular cGAMP and ATP. Here, we propose selective genetic and chemical biology approaches: we will characterize genetic tools that selectively abolish ENPP1’s hydrolase activity toward extracellular cGAMP but not ATP (dENPP1cGAMP); in parallel we will develop substrate- specific ENPP1 inhibitors as tool compounds and potential immunotherapeutics. In Aim 1, we will fully characterize the kinetics, selectivity, and mechanisms of action of mutant dENPP1cGAMP, as well as the pathophysiology of dEnpp1cGAMP mice. In Aim 2, we will evaluate multiple tumor models in the dEnpp1cGAMP mouse strain to determine the physiological roles of extracellular cGAMP in controlling tumor growth and synergism with checkpoint blockers. In Aim 3, we will first characterize mechanism of substrate selectivity of our lead cGAMP-selective ENPP1 inhibitor and then use this inhibitor to harness the anti-tumoral effects of extracellular cGAMP. This proposal combines careful biochemical analyses with mouse genetics and tool compound development to address the role of extracellular cGAMP in cancer, with the goal of improving cancer immunotherapy.


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 = $500,645 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$50,064
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	4/10/2025	NON-COMPETING CONTINUATION	$450,581
														Subtotal = $500,645

Issue Date FY: 2024 ( Subtotal = $475,613 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$25,032
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	4	3/7/2024	NON-COMPETING CONTINUATION	$450,581
														Subtotal = $475,613

Issue Date FY: 2023 ( Subtotal = $490,632 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	3	9/19/2023	NON-COMPETING CONTINUATION	$0
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	3	3/23/2023	NON-COMPETING CONTINUATION	$490,632
														Subtotal = $490,632

Issue Date FY: 2022 ( Subtotal = $490,632 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	2	3/23/2022	NON-COMPETING CONTINUATION	$450,579
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	001	2	5/23/2022	NON-COMPETING CONTINUATION	$40,053
														Subtotal = $490,632

Issue Date FY: 2021 ( Subtotal = $501,670 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	1	3/19/2021	NEW	$501,670
														Subtotal = $501,670

Grand Total All Awards = $2,459,192

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Investigating the roles of extracellular cGAMP and harnessing it for cancer treatment

Award Number: R01CA258427

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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