Effective therapeutic targeting of <i>CTNNB1</i> ‐mutant hepatoblastoma with <scp>WNTinib</scp>

Hepatoblastoma (HB), the most frequent pediatric liver cancer (2.16 cases/million), has surgery and perioperative chemotherapy as primary treatment, with severe lifelong side effects. This study evaluates the efficacy of the Wnt/CTNNB1 inhibitor WNTinib as a potential HB treatment, since CTNNB1 mutations occur in 70-90% of HBs. WNTinib's efficacy was assessed in three animal models (n = 48): (a) patient-derived xenograft (PDX) HB tumors (n = 5 CTNNB1-mutant, n = 1 CTNNB1 wild-type) implanted in NSG mice; (b) PDX-derived TT001- and (c) HepG2-HB cells subcutaneously implanted in Fox1<sup>nu</sup> mice; and in two patient-derived organoids from CTNNB1-mutant HBs. WNTinib delayed tumor growth in n = 4/5 CTNNB1-mutant PDX models and significantly improved survival versus controls (P = 0.03), with no effect in the wild-type model. Further, in the TT001 and HepG2 models, WNTinib reduced tumor growth (P < 0.05 and P = 0.002) and extended survival (P = 0.03 and P = 0.008), respectively. In HB organoids, WNTinib demonstrated greater efficacy than standard-of-care cisplatin (P = 0.009, org-1), and its antitumor effect was further enhanced when combined with chemotherapy (P = 0.01, org-1; P = 0.007, org-22). WNTinib delays tumor progression and increases survival in CTNNB1-mutated HB models, providing rationale to explore its use in human HB.

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Publication Details

Journal
Molecular Oncology
Published
2025-12-08
DOI
https://doi.org/10.1002/1878-0261.70168
Primary Topic
Wnt/β-catenin signaling in development and cancer
Type
article
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article

Effective therapeutic targeting of CTNNB1 ‐mutant hepatoblastoma with WNTinib

Agavni Mesropian, Alex Rialdi, Carla Montironi, Vanessa Del Pozo et al.
Molecular Oncology
Wnt/β-catenin signaling in development and cancer
article

Effective therapeutic targeting of CTNNB1 ‐mutant hepatoblastoma with WNTinib

Agavni Mesropian, Alex Rialdi, Carla Montironi, Vanessa Del Pozo, Albert Gris‐Oliver, Jordi Abril‐Fornaguera, Pau Sancho‐Bru, Ugne Balaseviciute, Peter Houghton, Roser Pinyol, Laura Zanatto, Josep Maria Llovet, Ieva Keraite, Ernesto Guccione, Elisa Fernández‐Martínez, Júlia Huguet‐Pradell, Swan N. Thung, Carolina Armengol
article en

Abstract

Hepatoblastoma (HB), the most frequent pediatric liver cancer (2.16 cases/million), has surgery and perioperative chemotherapy as primary treatment, with severe lifelong side effects. This study evaluates the efficacy of the Wnt/CTNNB1 inhibitor WNTinib as a potential HB treatment, since CTNNB1 mutations occur in 70-90% of HBs. WNTinib's efficacy was assessed in three animal models (n = 48): (a) patient-derived xenograft (PDX) HB tumors (n = 5 CTNNB1-mutant, n = 1 CTNNB1 wild-type) implanted in NSG mice; (b) PDX-derived TT001- and (c) HepG2-HB cells subcutaneously implanted in Fox1<sup>nu</sup> mice; and in two patient-derived organoids from CTNNB1-mutant HBs. WNTinib delayed tumor growth in n = 4/5 CTNNB1-mutant PDX models and significantly improved survival versus controls (P = 0.03), with no effect in the wild-type model. Further, in the TT001 and HepG2 models, WNTinib reduced tumor growth (P < 0.05 and P = 0.002) and extended survival (P = 0.03 and P = 0.008), respectively. In HB organoids, WNTinib demonstrated greater efficacy than standard-of-care cisplatin (P = 0.009, org-1), and its antitumor effect was further enhanced when combined with chemotherapy (P = 0.01, org-1; P = 0.007, org-22). WNTinib delays tumor progression and increases survival in CTNNB1-mutated HB models, providing rationale to explore its use in human HB.

Molecular Oncology
Institució Catalana de Recerca i Estudis Avançats (ES), The University of Texas at San Antonio Health Science Center (US), Departament de Salut (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Clínic de Barcelona (ES), Tisch Hospital (US), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Center for Migration Studies of New York (US), Children's Cancer Center (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Medical Research Network (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 65%
Wnt/β-catenin signaling in development and cancer
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