@article{61212afaa0ff40a0ac7a8d719928a754,
title = "IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage",
abstract = "Background & Aims: IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway. Methods: An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC. Results: Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p = 0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p = 0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR < 0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis. Conclusions: Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.",
keywords = "A12, Hepatocellular carcinoma, IGF signaling, Molecular therapy, miR-100",
author = "Victoria Tovar and Clara Alsinet and Augusto Villanueva and Yujin Hoshida and Chiang, {Derek Y.} and Manel Sol{\'e} and Swan Thung and Susana Moyano and Sara Toffanin and Beatriz M{\'i}nguez and Laia Cabellos and Judit Peix and Myron Schwartz and Vincenzo Mazzaferro and Jordi Bruix and Llovet, {Josep M.}",
note = "Funding Information: Augusto Villanueva is the recipient of a Sheila Sherlock fellowship. Beatriz Minguez is supported by a grant from Instituto de Salud Carlos III (FIS-CM04/00044). Vincenzo Mazzaferro and Sara Toffanin are supported by the Italian Association for Cancer Research and the Italian National Ministry of Health. Jordi Bruix is supported by a grant from Instituto Carlos III (ISCIII/FIS PI 05-0150). Josep M. Llovet is supported by grants from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (SAF-2007-61898). Funding Information: The authors who have taken part in this study declared that they do not have anything to declare regarding funding from industry or conflict of interest with respect to this manuscript. A.V. is the recipient of a Sheila Sherlock fellowship. B.M. is supported by a grant from Instituto de Salud Carlos III ( FIS-CM04/00044 ). V.M. and S.T. are supported by the Italian Association for Cancer Research and the Italian National Ministry of Health . J.B. is supported by a grant from Instituto Carlos III ( ISCIII/FIS PI 05-0150 ). J.M.L. is supported by grants from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases ( 1R01DK076986-01 ), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute ( SAF-2007-61898 ). We thank Dr. Rubini for kindly providing the antibody anti-IGF-1R pY1316. ImClone Systems Incorporated supplied the monoclonal antibody A12 used in this study. ",
year = "2010",
month = apr,
doi = "10.1016/j.jhep.2010.01.015",
language = "English",
volume = "52",
pages = "550--559",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier B.V.",
number = "4",
}