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The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53

Award Number: R01CA272753
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53 - Project Summary/Abstract The tumor suppressor p53 is often referred to as the “guardian of the genome”. Mutations of the p53 gene occur in ~50% of human cancer and loss of p53 function is known to play a central role in tumor progression and metastasis. Upon exposure to a stress signal, such as DNA damage, p53 transcription factor is activated and then induces an array of pro-survival and pro-death genes. Due to its potent role in tumor suppression, p53 is an attractive target for the development of new anticancer drugs. Nerve injury-induced protein 1 (Ninjurin1, NINJ1) and NINJ2 constitute the Ninjurin family of cell adhesion molecules and have been implicated in various pathological processes such as immune response. However, the role of NINJ1 and NINJ2 in tumorigenesis is unclear. We showed previously that NINJ1 is a target of p53 and in turn represses p53 mRNA translation. Thus, NINJ1 and p53 forms a negative feedback loop. Notably, our pilot study showed that NINJ1 and NINJ2 interact with each other through their N-terminal extracellular domains. We also found that like NINJ1, NINJ2 forms a negative regulatory loop with p53. To determine the biological significance of the NINJ1-NINJ2-p53 loop, we showed that: (1) loss of NINJ1 or NINJ2 inhibits cell migration and formation of tumor spheres and colonies in breast cancer cells and promote cellular senescence in mouse embryonic fibroblasts in a p53- dependent manner; (2) mice deficient in Ninj1 or Ninj2 are prone to chronic inflammation, which is likely due to enhanced pyroptosis through wild-type p53-dependent activation of NLRP3 inflammasome; (3) two small peptides, called Pep-1A and Pep-2A derived from N-terminal alpha helix domain of NINJ1 and NINJ2 protein were able to disrupt the formation of NINJ1-NINJ2 complex and elicit growth suppression. These observations prompt us to hypothesize that both NINJ1 and NINJ2 play a critical role in tumorigenesis through the p53 pathway. To test this, we will determine: (1) the feedback regulatory loops between NINJ1 and NINJ2 and between p53 and the Ninjurin family; (2) the biological significance of the NINJ1-NINJ2-p53 loop in tumor suppression; (3) whether the Ninj1- Ninj2-p53 loop can be targeted to kill tumor cells carrying wild-type p53.


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 = $436,503 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	4	5/23/2025	NON-COMPETING CONTINUATION	$436,503
														Subtotal = $436,503

Issue Date FY: 2024 ( Subtotal = $416,902 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	3	5/15/2024	NON-COMPETING CONTINUATION	$416,902
														Subtotal = $416,902

Issue Date FY: 2023 ( Subtotal = $431,473 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	2	5/26/2023	NON-COMPETING CONTINUATION	$431,473
														Subtotal = $431,473

Issue Date FY: 2022 ( Subtotal = $438,940 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Biology Research	000	1	6/20/2022	NEW	$438,940
														Subtotal = $438,940

Grand Total All Awards = $1,723,818

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The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53

Award Number: R01CA272753

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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