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Targeting the FBXO44/SUV39H1 Pathway in Cancer

Award Number: R01CA267103
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Targeting the FBXO44/SUV39H1 Pathway in Cancer - PROJECT SUMMARY Repetitive elements (REs) compose ~45% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through a high-content RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound repressive H3K9me3-modified nucleosomes at the replication fork and recruited H3K9me3 methyltransferase SUV39H1, ubiquitin ligase CRL4RBBP4/7, and histone deacetylase and chromatin-remodeling complex Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition transcriptionally activated satellite repeats and endogenous retroviruses and retrotransposons in cancer cells, leading to DNA replication stress and stimulation of MAVS and STING intracellular antiviral pathways to promote decreased tumorigenicity and enhanced immunotherapy response. In silico analysis revealed that FBXO44 expression inversely correlated with DNA replication stress, antiviral pathways, and cytotoxic T and natural killer (NK) cell infiltration in human cancers. Importantly, we found that FBXO44/SUV39H1 are dispensable for RE silencing in normal cells and their inhibition did not affect H3K9me3 levels at REs or cell viability. Our hypothesis is that FBXO44/SUV39H1-mediated RE element silencing is an epigenetic vulnerability of cancer cells that could potentially be targeted to induce viral mimicry responses that inhibit tumor growth and progression and enhance the efficacy of certain cancer therapies. In this proposal, we will perform preclinical studies that evaluate two potential therapeutic applications of FBXO44/SUV39H1 pathway targeting in cancer: 1) prevention of metastatic relapse through stimulation of intracellular antiviral pathways and NK cell recognition; and 2) enhancement of PARP inhibitor efficacy through induction of extensive DNA replication stress at REs. Moreover, we will investigate the role of the CRL4RBBP4/7 ubiquitin ligase in FBXO44/SUV39H1-mediated RE silencing and evaluate its targeting for cancer treatment. These studies could uncover a targetable epigenetic vulnerability of cancer cells whose inhibition induces viral mimicry to prevent tumor growth and progression and enhance the efficacy of cancer therapeutics, undoubtedly leading to a significant reduction in disease mortality.


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 = $446,063 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	4	11/13/2024	NON-COMPETING CONTINUATION	$401,456
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	001	4	6/4/2025	NON-COMPETING CONTINUATION	$44,607
														Subtotal = $446,063

Issue Date FY: 2024 ( Subtotal = $423,760 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$22,304
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	3	11/30/2023	NON-COMPETING CONTINUATION	$401,456
														Subtotal = $423,760

Issue Date FY: 2023 ( Subtotal = $437,141 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$437,141
														Subtotal = $437,141

Issue Date FY: 2022 ( Subtotal = $441,716 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	12/10/2021	NEW	$441,716
														Subtotal = $441,716

Grand Total All Awards = $1,748,680

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Targeting the FBXO44/SUV39H1 Pathway in Cancer

Award Number: R01CA267103

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/10/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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