Abstract PO009: Identification of IGF2 as genomic driver and actionable therapeutic target in hepatoblastoma
Authors: Abril-Fornaguera Jordi , Torrens Laura , Carrillo-Reixach Juan , Rialdi Alex , Balaseviciute Ugne , Huguet-Pradell Júlia , Montironi Carla , Haber Philipp , Del Río-Álvarez Álvaro , Domingo-Sàbat Montserrat , Royo Laura , Akers Nicholas , Willoughby Catherine E , Peix Judit , Torres-Martin Miguel , Puigvehi Marc , Pinyol Roser , 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 
Published: September 2022

Abstract
Background and Aims: Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens, commonly cisplatin. Here, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB.Methods: Paired tumor and adjacent tissues from 31 resected HBs and a validation set of 50 HBs were analyzed at the transcriptomic, genomic and epigenomic level using RNAseq, SNP and methylation arrays, respectively. The main targetable driver in HB was identified by gene co-expression network analysis (GCN) and its overexpression was confirmed by qRT-PCR. The anti-tumor effect of driver inhibition with molecular therapies alone or in combination with cisplatin was assessed in cell lines, patient-derived HB organoids and in a HB xenograft murine model.Results: Seven network modules were significantly deregulated in tumors compared to non-tumoral samples, including IGF2 signaling pathway, cell cycle and survival and immune response. IGF2 overexpression (FC&gt; 4 vs adjacent tissue) was identified as the top targetable HB driver (study cohort: 71%, 22/31; independent validation cohorts: 78% and 76%). IGF2high tumors displayed progenitor cell features and were significantly enriched in molecular classes with aggressive phenotypes and CTNNB1 mutations, while IGF2low tumors were enriched in inflammatory and TGF-β signaling. IGF2high tumors correlated with shorter recurrence-free survival after resection (median 34 months vs not reached for IGF2low; p = 0.02). IGF2 overexpression correlated in most cases (86%) with fetal promoter hypomethylation (50%), 11p15.5 loss of heterozygosity (LOH, 57%) or overexpression of miR483 (55%). Xentuzumab (anti-IGF1/2 mAb) alone or combined with cisplatin reduced proliferation and clonogenic capacity in IGF2high cell lines. The combination of xentuzumab and cisplatin exhibited synergistic effects in terms of cell viability in organoids derived from IGF2high human HBs. The combination treatment induced apoptosis and reduced IGF2 pathway activation in vitro. In mice (n = 13-14 per arm), this combination induced a significant decrease in the viable tumor volume (p &lt; 0.01), extended survival compared to cisplatin alone (p &lt; 0.05) and inhibited tumor angiogenesis (p &lt; 0.05).Conclusion: IGF2 is an actionable driver in HB and its overexpression was associated with fetal promoter hypomethylation, LOH or miR483 overexpression. The combination of a mAb against IGF1/2 (xentuzumab) with cisplatin led to remarkable anti-tumoral effects in pre-clinical models, providing the rationale for exploring this regimen in IGF2high HB patients.
Citation Format: Jordi Abril-Fornaguera, Laura Torrens, Juan Carrillo-Reixach, Alex Rialdi, Ugne Balaseviciute, Júlia Huguet-Pradell, Carla Montironi, Philipp Haber, Álvaro Del Río-Álvarez, Montserrat Domingo-Sàbat, Laura Royo, Nicholas Akers, Catherine E Willoughby, Judit Peix, Miguel Torres-Martin, Marc Puigvehi, Roser Pinyol, Stefano Cairo, Margaret Childs, Rudolf Maibach, Rita Alaggio, Piotr Czauderna, Bruce Morland, Bojan Losic, Vincenzo Mazzaferro, Ernesto Guccione, Daniela Sia, Carolina Armengol, Josep M Llovet. Identification of IGF2 as genomic driver and actionable therapeutic target in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO009.