# Targeting the Cancer Glycocalyx

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $429,494

## Abstract

PROJECT SUMMARY
Cell surface glycans mediate interactions with receptors on other cells, in the extracellular matrix, or on the
same cell membrane. Altered glycosylation has long been known as a hallmark of cancer. Two frequently
observed cancer-associated phenotypes are hypersialylation and mucin overexpression. These cancer
glycosignatures strongly correlate with disease aggressiveness and poor patient outcomes, but their functional
contribution to cancer progression has been unclear. The broad objective of this program is to bring
chemical tools to bear on this important problem in oncology, with an eye for developing new modes
of intervention. An enabling tool for these studies are synthetic glycopolymers that we used to engineer
discrete glycosylation patterns on live cells, or to engage specific glycan-binding proteins in a multivalent
manner.
In the previous granting period we made three major discoveries regarding the roles of cancer
glycosignatures in disease: (1) Hypersialylation is a mechanism of immune evasion mediated through the
Siglec family of sialic acid-binding immune cell receptors. Accordingly, immune cell killing of cancer cells can
be potentiated by targeted cleavage of their cell-surface sialosides using antibody-sialidase conjugates. (2)
Mucin overexpression enhances the thickness and stiffness of the glycocalyx, which promotes integrin
clustering and focal adhesion signaling. This, in turn, enhances cell survival in vitro and promotes metastasis in
mouse tumor models. And finally, (3) a glycan switching mechanism modulates partitioning of galectin-1, a
prominent breast cancer marker, between a cell's glycocalyx and nucleus. Nuclear localization of galectin-1
drives breast cancer invasion, and this is inhibited by glycopolymers that sequester galectin-1 extracellularly.
These discoveries form the foundation of the aims proposed in this renewal application. Aim 1 is a
corollary to our discovery that cancer mucins drive oncogenesis. We will develop antibody-enzyme conjugates
comprising mucin-specific proteases (aka “mucinases”) to deforest cancer cells. We will generate tool
molecules using known bacterial mucinases, and also identify human mucinases for incorporation into
therapeutic candidates. In Aim 2, we will construct next-generation glycopolymers with native polypeptide
backbones. These will be employed for fundamental studies of cancer glycobiology and for translational
applications in Aim 3. Finally, in Aim 3 we introduce a new strategy for targeting extracellular proteins for
degradation using glycopolymers that hijack the mannose-6-phosphate receptor (M6PR) lysosomal trafficking
pathway. We will construct antibody-M6P glycopolymer conjugates that bind oncogenic cell-surface molecules
such as growth factor receptors and the cancer-associated mucin MUC1 and target them for lysosomal
degradation via engagement of M6PR. This new therapeutic modality complements the popular PROTAC
approach for targeting intracellular p...

## Key facts

- **NIH application ID:** 9878080
- **Project number:** 5R01CA227942-19
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Carolyn Bertozzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,494
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878080

## Citation

> US National Institutes of Health, RePORTER application 9878080, Targeting the Cancer Glycocalyx (5R01CA227942-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878080. Licensed CC0.

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