Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Targeted degradation of glycoimmune checkpoints Siglec-7 and -9 for cancer immunotherapy

Award Number: R01CA304089
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/19/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

Group Awards By:

View Award Description

Targeted degradation of glycoimmune checkpoints Siglec-7 and -9 for cancer immunotherapy - PROJECT SUMMARY/ABSTRACT Targeted degradation of extracellular proteins is a new direction in drug discovery. In this approach, a heterobifunctional molecule is used to recruit a target protein of interest to the proteosome or lysosome for degradation. Typically, only one membrane protein can be targeted for degradation at a time. Using SuFEx click chemistry, we have discovered a ligand that binds with exclusive specificity to the newly discovered glycoimmune checkpoints Siglec-7 and -9. In this project, we will test the hypothesis that a heterobifunctional degrader constructed with such ligands can simultaneously target both Siglecs to the lysosome for degradation. In the tumor microenvironment, Siglec-7 and Siglec-9 are predominantly expressed by myeloid cells, the most abundant immune cells infiltrating solid tumors, including melanoma and pancreatic cancer. These Siglecs are not only involved in suppressing macrophage-mediated phagocytosis of tumor cells, but also in inhibiting T cell activity, operating in a way which is orthogonally to CTLA-4 and PD-1. When T cells interact with neighboring myeloid cells, such as dendritic cells and macrophages, they acquire Siglec-7 and -9 through a process called trogocytosis, resulting in impaired T cell activation and effector function. Therefore, we hypothesize that degradation of Siglec-7 and -9 could be used alone or in combination with FDA-approved immune checkpoint blockade to treat anti-PD-1 or anti-CTLA-4 refractory tumors In Aim 1 of this project, we will construct an unnatural sialic acid derivative library and use a cell-based assay to identify improved ligands with high affinity and exclusive specificity for Siglec-7 and Siglec-9. These optimized ligands will be used to construct degraders that specifically target and degrade both Siglecs. The degradation efficacy, pharmacokinetics and toxicity of these degraders will be determined. Subsequently, the therapeutic potential and mechanism of action of the degraders will be evaluated both in vitro and in humanized mouse tumor models with a focus on melanoma and pancreatic cancer (Aim 2). The degraders will be tested alone or in combination with other immunomodulatory agents, such as anti-PD-1 or anti-CTLA-4. Finally, in Aim 3, the ability of these degraders to induce Siglec-7 and -9 degradation will be further investigated using cultured pancreatic cancer patient tumor slices. The resulting effects on macrophage- and T- cell-mediated tumor control will be examined.


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 = $748,410 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Treatment Research	000	1	6/23/2026	NEW	$748,410
														Subtotal = $748,410

Grand Total All Awards = $748,410

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeted degradation of glycoimmune checkpoints Siglec-7 and -9 for cancer immunotherapy

Award Number: R01CA304089

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/19/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer