# Targeting the cancer glycocalyx

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $503,708

## Abstract

PROJECT SUMMARY
 Altered cell-surface glycosylation is recognized as a hallmark of cancer. Two frequently observed cancer-
associated glyco-phenotypes are hypersialylation and mucin overexpression. These cancer glycosylation
patterns strongly correlate with disease aggressiveness and poor patient outcomes, but until recently their
functional significance was unclear.
 In previous funding periods, we discovered that hypersialylation allows cancer cells to evade immune
surveillance through engagement of immune inhibitory Siglec receptors. We speculate that poor responses of
cancer patients to current immune therapies, including monoclonal antibodies, T cell checkpoint receptor
blockade, bispecific T cell engagers and targeted cell therapies, are due to immune suppression via the
Siglec/sialoglycan axis. Accordingly, we developed a new class of immune therapies comprising antibody-
sialidase conjugates that degrade Siglec ligands on targeted cancer cells.
 In collaborative work, we found that mucin glycoproteins promote focal adhesion formation and enhance
cancer cell survival and proliferation in the metastatic niche by virtue of their bulk physical properties. We also
discovered that certain cancer-associated mucin glycoforms engage Siglec receptors thereby mediating immune
suppression. These dual functions of cancer mucins make them attractive targets for cancer therapy.
Accordingly, we made targeted mucin degraders comprising mucin-specific proteases fused to cancer antigen-
binding nanobodies. Nanobody-mucinase fusions had anti-metastatic and immune potentiating activities in
mouse cancer models.
 In the next funding period, we will build on these discoveries with three Specific Aims. In Aim 1, we will
develop targeted mucin degraders based on engineered human proteases, an important step toward clinical
translation. In Aim 2, we will explore a new approach to precision targeting of mucin degraders to shed and
secreted mucins that are immune suppressive in circulation. Finally, in Aim 3 we will develop a new cancer
immune therapy modality comprising antibody-lectin chimeras (AbLecs). These bispecific molecules
simultaneously bind cancer antigens, block immune suppressive glycan ligands, and mediate immune effector
functions via their Fc domains. Overall, the proposed work will set the stage for preclinical development
of two new therapeutic strategies targeting the cancer glycocalyx.

## Key facts

- **NIH application ID:** 10881159
- **Project number:** 2R01CA227942-23
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Carolyn Bertozzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,708
- **Award type:** 2
- **Project period:** 2019-03-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881159

## Citation

> US National Institutes of Health, RePORTER application 10881159, Targeting the cancer glycocalyx (2R01CA227942-23). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881159. Licensed CC0.

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