Effective therapeutic targeting of CTNNB1 ‐mutant hepatoblastoma with WNTinib
Year: 2025
Type: article
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 nu 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.
Source: Molecular Oncology
Authors: Ugne Balaseviciute, Júlia Huguet‐Pradell, Jordi Abril‐Fornaguera, Albert Gris‐Oliver, Alex Rialdi, Elisa Fernández‐Martínez, Carla Montironi, Vanessa Del Pozo, Peter Houghton, Laura Zanatto, Agavni Mesropian, Ieva Keraite, Swan Thung, Carolina Armengol, Pau Sancho‐Bru, Ernesto Guccione, Roser Pinyol, Josep M. Llovet
Institutions: Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Tisch Cancer Institute, Universitat de Barcelona, Icahn School of Medicine at Mount Sinai, The University of Texas at San Antonio Health Science Center, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Institució Catalana de Recerca i Estudis Avançats
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,300
Funders: Samuel Waxman Cancer Research Foundation, Asociación Española para el Estudio del Hígado, Worldwide Cancer Research, Centres de Recerca de Catalunya, Georgia Clinical and Translational Science Alliance, Florida Polytechnic University, Cancer Research UK, European Commission, Generalitat de Catalunya, Federación Española de Enfermedades Raras, Ministerio de Ciencia e Innovación, Associazione Italiana per la Ricerca sul Cancro, Universitat de Barcelona, European Association for the Study of the Liver, Societat Catalana de Digestologia, CRIS Cancer Foundation, National Institutes of Health, HORIZON EUROPE Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Agencia Estatal de Investigación, National Center for Advancing Translational Sciences
Awards: Hepatic autophagy, progenitor cells and fibrosis, G1079996559, G1307865877, G1383933008, G1551200932, G2372073742, G2660406951, G3085999528, G3194319764, G3480869486, G3518538256, G3665773225, G3725615782, G3881485945, Big Omics Data Engine 2 Supercomputer, G461880780, G5314622356, G5482073511, G6177305277, G6437317185, G679576189, G7084143925, An immunocompetent platform for the characterization and discovery of novel therapeutics for hepatocellular carcinoma, G738160294, G7701860573, TUMOUR-HOST INTERACTIONS IN LIVER CANCER OF CHILDHOOD AND ADULTS, COVID and Translational Science supercomputer (CATS), G8556467429, G8612193037, G8677975238, G8681408770, G8920660035, G9000068469, G9000136890, G9000139263, G9000185558, Determinants of immunotherapy response in NASH-Hepatocellular carcinoma
OpenAlex ID: W4417128154