Effective therapeutic targeting of CTNNB1-mutant hepatoblastoma with WNTinib.

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.