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Mechanistic insight into tumor-associated MUC1 glycopeptides binding to macrophage galactose-type lectin

Award Number: R15CA242351
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2019
PERIOD OF PERFORMANCE END DATE: 12/30/2026

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Mechanistic insight into tumor-associated MUC1 glycopeptides binding to macrophage galactose-type lectin - PROJECT SUMMARY MUC1, the heavily glycosylated cell-surface mucin, is altered in both expression and glycosylation patterns in human carcinomas of the epithelium. Tumor-specific glycopeptide epitopes of MUC1 are recognized by a variety of lectin receptors on immune cells. These interactions have not been extensively studied, despite the fact that aberrant tumor glycosylation alters how the immune system perceives the tumor and can also induce immunosuppressive signaling leading to the creation of a pro-tumor microenvironment favoring tumor progression and metastasis. In addition, it has recently been proposed that the tumor glycocode may be considered a novel immune checkpoint. In this renewal application, we will continue to examine epitope heterogeneity, the glycoside cluster effect, and the steric hindrance effect of neighboring glycans on binding to lectins (Aim 1). Specifically, we will focus on the design of novel synthetic tools such as a) structurally well- defined MUC1 glycopeptides with varying multivalency and b) MUC1-derived positional scanning synthetic glycopeptide combinatorial library (PS-SGCL) displaying native-like heterogeneous and aberrant O-glycan epitopes, sialylated Tn and Thomsen–Friedenreich (TF) antigens. The thermodynamic profile of the interaction of MUC1-derived glycopeptides with macrophage galactose-specific lectin (hMGL) and Siglecs (-7, -9 and/or - 15) will be assessed by ITC. The binding kinetics will be determined by direct measurement of the strength of unbinding of receptor-ligand interactions by AFM (Aim 2). We are particularly interested in how protein scaffold contributes to the interactions with lectins and also the role of water in protein hydration and the binding complex formation with the ligand. All these are known variables that may impact the receptor targeting efficacy and immune response induced by immune cells. Furthermore, this renewal application proposes to use MUC1 glycopeptides and PS-SGCLs in the discovery and assessment of binding specificities of anti-MUC1 antibodies found in sera from cancer patients with MUC1+ tumors (Aim 3). We are focusing on the identification of a new class of antibodies targeting dynamic glycopeptide neoepitopes . In addition to the research aims, we will continue to recruit the next generation of scientists into the glycoscience field by offering exciting research opportunities for undergraduate and graduate students at the interface of chemistry and immunology. In summary, the proposed study will facilitate a deeper understanding of the principles of glycan-protein interactions and general rules that govern the ability of lectins to regulate immune response by engaging glycoproteins on the cell surface. This may constitute an important roadmap for translating fundamental MUC1 glycobiology knowledge toward next-generation cancer immunotherapies.


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 = $0 )
2025	2024	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Cancer Biology Research	000	2	10/1/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $443,151 )
2024	2024	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Cancer Biology Research	000	2	12/26/2023	COMPETING CONTINUATION	$443,151
2024	2024	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Cancer Biology Research	002	2	1/12/2024	COMPETING CONTINUATION	$0
2024	2019	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Cancer Biology Research	001	1	1/12/2024	NEW	$0
														Subtotal = $443,151

Issue Date FY: 2019 ( Subtotal = $434,970 )
2019	2019	FLORIDA ATLANTIC UNIVERSITY	777 GLADES RD	BOCA RATON	FL	33431	PALM BEACH	USA	Cancer Biology Research	000	1	7/8/2019	NEW	$434,970
														Subtotal = $434,970

Grand Total All Awards = $878,121

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Mechanistic insight into tumor-associated MUC1 glycopeptides binding to macrophage galactose-type lectin

Award Number: R15CA242351

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2019

PERIOD OF PERFORMANCE END DATE: 12/30/2026

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