# Novel anti-cancer biologics targeting Wnt signaling pathway

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2020 · $180,254

## Abstract

Project Summary 
Wnt signaling regulates cell replication and proliferation of most adult stem cells, and its 
abnormal activation has been linked to many cancers. Both small-molecular inhibitors that 
inhibit Wnt production and blocking antibodies against the Wnt receptor Frizzled (FZD) have 
been developed, and some are currently in clinical trials. Humans express 19 Wnt and 10 Wnt 
receptor Frizzed proteins (FZDs), and each tissue type may have its own profile of Wnt-FZD 
pairs. As Wnt is critical for maintaining almost all adult stem cells, a major challenge is to 
minimize the side effects to healthy tissues. One approach to protecting these tissues is to 
develop blocking agents that specifically target the particular set of Wnt-FZD pair(s) expressed 
in the cancer tissues being targeted. However, this has proven difficult, as both Wnt and FZD 
family members are highly conserved. In particular, a specific and effective blocking agent 
targeting FZD7, which is upregulated in triple-negative breast cancer, has yet to be established. 
Here we propose to develop a novel class of therapeutic proteins that are highly effective in 
blocking Wnt signaling mediated by FZD1/2/7 (these three share almost-identical Wnt-binding 
domains). This is based on our previous finding that a bacterial toxin, C. difficile toxin B (TcdB), 
binds to FZD1/2/7 as its high-affinity receptor, and its binding to FZD1/2/7 potently inhibits Wnt 
signaling. Our preliminary studies showed that the FZD-binding domain of TcdB (TcdBFBD) 
inhibits growth in a mouse triple-negative breast cancer organoid in vitro and xenograft model in 
vivo, without damaging Wnt-sensitive tissues. We propose to use protein engineering to 
improve the biochemical and pharmacological properties of TcdBFBD, and to further evaluate the 
therapeutic potential of TcdBFBD using xenograft models and human breast cancer organoids. 
These studies will further establish Wnt signaling as an important therapeutic target, and 
develop a new class of therapeutic proteins for labeling and treating Wnt-dependent tumors.

## Key facts

- **NIH application ID:** 9833519
- **Project number:** 5R21CA235533-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Min Dong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $180,254
- **Award type:** 5
- **Project period:** 2018-12-07 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833519

## Citation

> US National Institutes of Health, RePORTER application 9833519, Novel anti-cancer biologics targeting Wnt signaling pathway (5R21CA235533-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9833519. Licensed CC0.

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