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A novel Frizzled 7 antibody disrupts the Wnt pathway and inhibits Wilms tumor growth
Einav Vax1,2, Revital Caspi1,2,3, Rachel Shukrun1,2,3
1Pediatric Stem Cell Research Institute, Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
Abstract:
Frizzled 7 (FZD7), a Wnt receptor that activates canonical Wnt/β-catenin signaling, has been implicated in multiple cancers, including Wilms tumor (WT), the most common pediatric kidney malignancy. We previously identified FZD7 as a marker of the WT cancer stem cell population and a potential therapeutic target. To evaluate this, we generated a panel of monoclonal anti-FZD7 antibodies using epitope mapping of the receptor and assessed their functional activity in primary WT cells and xenograft models. Among the panel, clone 288.1 induced significant cell death in primary Wilms tumor cells and inhibited cell proliferation and migration. This effect correlated with canonical Wnt signaling inhibition, a reduction in activated β-catenin and downregulation of Wnt/β-catenin target genes concomitant with diminished Wilms tumor cancer stem cell (CSC) markers. In vivo, treatment with anti-FZD7-288.1 significantly inhibited WT xenograft growth, resulting in reduced tumor volume. These findings demonstrate that FZD7 is a critical driver of Wilms tumor progression and support antibody-mediated FZD7 blockade as a promising therapeutic strategy.
Insights
This study shows Frizzled 7 (FZD7) drives Wilms tumor (WT) progression. Blocking FZD7 with an antibody (288.1) effectively reduced WT cell growth and tumor size, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Frizzled 7 (FZD7) receptor activates Wnt/β-catenin signaling and is implicated in Wilms tumor (WT).
- FZD7 was previously identified as a Wilms tumor cancer stem cell marker and potential therapeutic target.
Purpose of the Study:
- To generate and evaluate monoclonal antibodies targeting FZD7 for Wilms tumor therapy.
- To assess the functional activity of anti-FZD7 antibodies in Wilms tumor cells and xenograft models.
Main Methods:
- Epitope mapping of FZD7 to generate monoclonal antibodies.
- Assessment of antibody functional activity in primary Wilms tumor cells and in vivo xenograft models.
- Analysis of Wnt/β-catenin signaling pathway components and cancer stem cell markers.
Main Results:
- Antibody clone 288.1 induced significant cell death, inhibited proliferation and migration in primary Wilms tumor cells.
- Anti-FZD7-288.1 treatment reduced activated β-catenin, downregulated Wnt/β-catenin target genes, and diminished Wilms tumor cancer stem cell markers.
- In vivo, anti-FZD7-288.1 significantly inhibited Wilms tumor xenograft growth and reduced tumor volume.
Conclusions:
- FZD7 is a critical driver of Wilms tumor progression.
- Antibody-mediated FZD7 blockade is a promising therapeutic strategy for Wilms tumor.
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