Table 1. Therapeutics targeting WNT signaling cascades.
| Class | Mechanism of action | Drug | Phase | Clinical Trial # | Features | Recruitment status and ESCD |
|---|---|---|---|---|---|---|
| [1] Pan-WNT signaling inhibitors | Porcupine inhibitor | RXC004* | Phase II Phase II |
NCT04907851 NCT04907539 |
Monotherapy Combo ICI |
Recruiting (June, 2023) Recruiting (August, 2023) |
| CGX1321 | Phase I | NCT02675946 | Monotherapy & Combo ICI | Recruiting (March, 2023) | ||
| ETC-159 | Phase I | NCT02521844 | Monotherapy & Combo ICI | Recruiting (August, 2024) | ||
| LGK974 | Phase I | NCT01351103 | Monotherapy & Combo ICI | Recruiting (November, 2023) | ||
| [2] Canonical WNT signaling inhibitors | β-catenin PPI inhibitor | PRI-724 | Phase I & II | NCT01606579 | Monotherapy | Completed in 2016 |
| E7386 | Phase I & II | NCT05091346 | Combo ICI | Recruiting (May, 2024) | ||
| β-catenin PROTAC | xStAx-VHLL | Preclinical | ||||
| [3] Noncanonical WNT signaling inhibitors | ROR1 inhibitor | KAN0439834 | Preclinical | |||
| KAN0441571C | Preclinical | |||||
| [4] Biologics targeting WNT receptors and signaling modulators | Anti-ROR1 mAb | Cirmtuzumab | Phase I & II | NCT03088878 | Combo BTK inhibitor | Active NR (June, 2027) |
| Anti-ROR1 ADC | VLS-101 | Phase II | NCT04504916 | Monotherapy | Recruiting (March, 2024) | |
| NBE-002 | Phase I & II | NCT04441099 | Monotherapy | Recruiting (December, 2025) | ||
| CS5001 | Phase I | NCT05279300 | Monotherapy | Recruiting (March, 2024) | ||
| ROR1-targeted CAR-T | LYL797 | Phase I | NCT05274451 | Monotherapy | Recruiting (September, 2026) | |
| R12 CAR | Phase I | NCT02706392 | Monotherapy | Terminated in 2021 | ||
| Anti-PTK7 ADC | PF-06647020 | Phase I | NCT04189614 | Monotherapy | Recruiting (August, 2023) | |
| Anti-DKK1 mAb | DKN-01 | Phase II | NCT04363801 | Combo ICI and/or CAPOX | Recruiting (June, 2023) | |
| Anti-FZD1/2/5/7/8 mAb | OMP-18R5 | Phase I | NCT01345201 | Monotherapy | Completed in 2014 | |
| FZD8-Fc fusion protein | OMP-54F28 | Phase I | NCT01608867 | Monotherapy | Completed in 2017 | |
| Anti-RSPO3 mAb | OMP-131R10 | Phase I | NCT02482441 | Combo FOLFIRI | Completed in 2018 | |
| Anti-LGR5 mAb | BNC101 | Phase I | NCT02726334 | Monotherapy | Terminated in 2018 |
Anti-RANKL monoclonal antibody (mAb) has been added to RXC004 to prevent therapy-induced bone loss. Abbreviations: Active NR, Active, not recruiting; ADC, antibody-drug conjugate; CAPOX, chemotherapy with capecitabine and oxaliplatin; CAR-T, chimeric antigen receptor-modified T cells; Clinical Trial #, clinical trial identifier in the ClinicalTrials.gov database (https://clinicaltrials.gov); Combo, combination therapy; ESCD, Estimated Study Completion Date; ICI, immune checkpoint inhibitor; FOLFIRI, chemotherapy with leucovorin, fluorouracil and irinotecan; FZD8-Fc fusion protein, WNT-ligand trap; PF-06647020, cofetuzumab pelidotin; PPI, protein–protein interaction; PROTAC, proteolysis targeting chimera; VLS-101, zilovertamab vedotin; xStAx-VHLL, xStAx stapled helical peptide coupled with von Hippel-Lindau protein ligand.