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Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

Award Number: R01CA258606
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/20/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy - Project Summary/Abstract Checkpoint blockade has revolutionized the field of cancer immunotherapy treatment, but many tumors remain unresponsive due to lack of effector T cell infiltration and activation in the tumor microenvironment. Innate immune priming of these “cold” tumors has emerged as a therapeutic strategy for increasing the efficacy of checkpoint blockade through stimulated type I interferon (IFN) production and downstream adaptive response. Recent efforts and ongoing clinical trials have focused on activation of the STING-dependent antiviral pathway to promote IFN production in the tumor microenvironment. However, many tumors downregulate STING signaling, and the therapeutic effects of STING agonists are thought to be mediated by their effects on tumor- infiltrating host myeloid cells. Our lab recently discovered that the DNA damage sensor DNA-PK triggers a STING-independent DNA sensing pathway (SIDSP) in human cells that potently activates IFN production in response to foreign DNA. We have developed synthetic superagonists of DNA-PK-dependent antiviral immunity that trigger potent antiviral responses in human melanoma cells that are unresponsive to STING agonists. We hypothesize that activation of the SIDSP within tumor cells will provide a unique signal to enhance inflammation within tumors and will stimulate potent immune responses. The goal of this proposal is to assess DNA-PK-SIDSP activation as a therapeutic strategy in human cancer. We will determine how DNA-PK directs distinct outcomes to DNA damage versus foreign DNA, and we will evaluate the therapeutic potential of triggering the DNA-PK-SIDSP in human tumors, in vitro and in vivo using cutting edge humanized mouse models. Our studies will uncover fundamental new aspects of the biology of the SIDSP, together with the first pre-clinical evaluation of DNA-PK activation as a novel 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 = $712,871 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	4	1/8/2025	NON-COMPETING CONTINUATION	$641,585
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	002	4	5/30/2025	NON-COMPETING CONTINUATION	$71,286
														Subtotal = $712,871

Issue Date FY: 2024 ( Subtotal = $681,404 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	3	4/19/2024	NON-COMPETING CONTINUATION	$35,864
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	3	12/14/2023	NON-COMPETING CONTINUATION	$645,540
														Subtotal = $681,404

Issue Date FY: 2023 ( Subtotal = $682,539 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$55,716
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	2	12/23/2022	NON-COMPETING CONTINUATION	$626,823
														Subtotal = $682,539

Issue Date FY: 2022 ( Subtotal = $718,598 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	000	1	1/20/2022	NEW	$718,598
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Biology Research	001	1	2/7/2022	NEW	$0
														Subtotal = $718,598

Grand Total All Awards = $2,795,412

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Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

Award Number: R01CA258606

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/20/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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