Identification of IGF2 as Genomic Driver and Actionable Therapeutic Target in Hepatoblastoma

• Published in: Molecular cancer therapeutics 2023-04, Vol.22 (4), p.485-498
• Main Authors: Abril-Fornaguera, Jordi, Torrens, Laura, Andreu-Oller, Carmen, Carrillo-Reixach, Juan, Rialdi, Alex, Balaseviciute, Ugne, Pinyol, Roser, Montironi, Carla, Haber, Philipp K, Del Río-Álvarez, Álvaro, Domingo-Sàbat, Montserrat, Royo, Laura, Akers, Nicholas K, Willoughby, Catherine E, Peix, Judit, Torres-Martin, Miguel, Puigvehi, Marc, Cairo, Stefano, Childs, Margaret, Maibach, Rudolf, Alaggio, Rita, Czauderna, Piotr, Morland, Bruce, Losic, Bojan, Mazzaferro, Vincenzo, Guccione, Ernesto, Sia, Daniela, Armengol, Carolina, Llovet, Josep M
• Format: Article
• Language: English
• Subjects: Animals; Cisplatin - pharmacology; Cisplatin - therapeutic use; DNA Methylation; Genomics; Hepatoblastoma - drug therapy; Hepatoblastoma - genetics; Hepatoblastoma - pathology; Humans; Insulin-Like Growth Factor II - genetics; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Mice
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-22-0335

Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.