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Decoding the functional pleiotropy of IL-20Rβ ligands in inflammation and tumorigenesis

Award Number: K22CA266531
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/20/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Decoding the functional pleiotropy of IL-20Rβ ligands in inflammation and tumorigenesis - Robert A. Saxton | K22 (PAR-18-467) | Project Summary / Abstract Although inflammation is essential for protecting organisms against infection, excessive or chronic inflammation is also associated with an increased risk of certain cancers. This is particularly true at epithelial barriers such as the colonic mucosa in the gastrointestinal (GI) tract, which are in frequent contact with the external environment and therefore particularly susceptible to damaging inflammatory responses. Indeed, over 20% of patients with inflammatory bowel disease (IBD) will go on to develop colitis-associated cancer (CAC). Moreover, most therapeutic options for autoinflammatory diseases like IBD involve the use of immunosuppressive drugs, which may also increase tumor incidence due to reduced immunosurveillance. An alternative approach is to exploit natural mechanisms of tissue protection and repair in order to reduce tumor-promoting inflammation without suppressing anti-tumor immune responses. Recently, several members of the IL-20 cytokine family have been shown to be upregulated in both IBD and GI cancers, but their functional roles in these contexts are not fully understood. This includes the cytokines IL-19, IL-20, and IL-24, all of which signal through the shared receptor subunit IL-20Rβ. However, whether this upregulation drives disease pathology or reflects a beneficial but insufficient homeostatic response remains unclear. This is largely due to the combinatorial and interconnected nature of receptor sharing within this family, resulting in a high degree of functional pleiotropy and redundancy that hinders experimental interrogation of these pathways. In this project, we will employ structure-guided protein engineering to deconvolute the pleiotropic functions of IL-20Rβ ligands in inflammation-associated colon cancer. We will first use a combination of directed evolution and structure-based rational protein design to develop a pharmacological toolkit, comprising IL-20 receptor agonists and antagonists with altered receptor specificities, allowing us to selectively modulate the activity of individual IL-20Rβ ligands. We will then use these tools in vivo to probe the effect of these engineered proteins in the development, progression, and gene expression changes over the course of colitis induction and tumor progression, using the well-established AOM/DSS mouse model of CAC. Together, these studies will provide important insights into the protective and pathogenic functions of distinct IL-20Rβ ligands in CAC, while also directly testing the therapeutic potential of our engineered cytokine variants in the prevention of inflammation associated cancer.


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: 2026 ( Subtotal = $0 )
2026	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Research Manpower	000	3	5/11/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $200,232 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Research Manpower	000	3	1/15/2025	NON-COMPETING CONTINUATION	$200,232
														Subtotal = $200,232

Issue Date FY: 2024 ( Subtotal = $200,232 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Research Manpower	000	2	2/28/2024	NON-COMPETING CONTINUATION	$200,232
														Subtotal = $200,232

Issue Date FY: 2023 ( Subtotal = $200,232 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Research Manpower	000	1	2/20/2023	NEW	$200,232
														Subtotal = $200,232

Grand Total All Awards = $600,696

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Decoding the functional pleiotropy of IL-20Rβ ligands in inflammation and tumorigenesis

Award Number: K22CA266531

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/20/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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