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Cellular and Molecular Biology

Abstract LB-233: IGF activation in a molecular subclass of hepatocellular carcinoma and preclinical efficacy of IGF-1R blockage

Victoria Tovar, Clara Alsinet, Augusto Villanueva, Yujin Hoshida, Derek Y. Chiang, Manel Solé, Swan Thung, Susana Moyano, Sara Toffanin, Beatriz Minguez, Laia Cabellos, Judit Peix, Myron Schwartz, Vincenzo Mazzaferro, Jordi Bruix and Josep M. Llovet
Victoria Tovar
1HCC translational research lab, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Clara Alsinet
2Divison of Liver Diseases, Mount Sinai School of Medicine, New York, NY
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Augusto Villanueva
1HCC translational research lab, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Yujin Hoshida
3Cancer Program, Broad Institute, Boston, MA
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Derek Y. Chiang
3Cancer Program, Broad Institute, Boston, MA
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Manel Solé
4Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Swan Thung
5Pathology Department, Mount Sinai School of Medicine, New York, NY
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Susana Moyano
4Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Sara Toffanin
2Divison of Liver Diseases, Mount Sinai School of Medicine, New York, NY
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Beatriz Minguez
2Divison of Liver Diseases, Mount Sinai School of Medicine, New York, NY
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Laia Cabellos
2Divison of Liver Diseases, Mount Sinai School of Medicine, New York, NY
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Judit Peix
1HCC translational research lab, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Myron Schwartz
6Surgical Oncology, Mount Sinai School of Medicine, New York, NY
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Vincenzo Mazzaferro
7Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy.
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Jordi Bruix
4Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
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Josep M. Llovet
2Divison of Liver Diseases, Mount Sinai School of Medicine, New York, NY
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DOI: 10.1158/1538-7445.AM10-LB-233 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Background: IGF signaling contributes to proliferation and cell survival through PI3K/AKT and MAPK pathways. It has a relevant role in a variety of human malignancies.

Aims: (1) To analyze the role of IGF signaling in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and (2) To asses the antitumoral activity of IGF pathway targeted therapies.

Methods: An integrative molecular dissection of the axis was performed in a cohort of 104 HCCs, including gene (quantitative PCR and Affymetrix U133 2.0® microarray) and miRNA expression (ligation-mediated amplification method), structural aberrations (Affymetrix STY Mapping Array®) and protein activation (immunohistochemistry). The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro through viability and proliferation assays. A xenograft model of HCC was used to evaluate A12 activity in vivo.

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-, 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 IGF2 overexpression (p=0.03), mTOR signaling (p=0.035) and was enriched in a molecularly distinct HCC subclass defined through unsupervised hierarchical clustering of the same cohort of samples (Proliferation subclass) (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 treated mice exhibited delayed tumor growth and prolonged survival in comparison to control mice, a reduction in proliferation rates and induction of apoptosis was observed in treated mice tumoral samples.

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.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-233.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract LB-233: IGF activation in a molecular subclass of hepatocellular carcinoma and preclinical efficacy of IGF-1R blockage
Victoria Tovar, Clara Alsinet, Augusto Villanueva, Yujin Hoshida, Derek Y. Chiang, Manel Solé, Swan Thung, Susana Moyano, Sara Toffanin, Beatriz Minguez, Laia Cabellos, Judit Peix, Myron Schwartz, Vincenzo Mazzaferro, Jordi Bruix and Josep M. Llovet
Cancer Res April 15 2010 (70) (8 Supplement) LB-233; DOI: 10.1158/1538-7445.AM10-LB-233

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Abstract LB-233: IGF activation in a molecular subclass of hepatocellular carcinoma and preclinical efficacy of IGF-1R blockage
Victoria Tovar, Clara Alsinet, Augusto Villanueva, Yujin Hoshida, Derek Y. Chiang, Manel Solé, Swan Thung, Susana Moyano, Sara Toffanin, Beatriz Minguez, Laia Cabellos, Judit Peix, Myron Schwartz, Vincenzo Mazzaferro, Jordi Bruix and Josep M. Llovet
Cancer Res April 15 2010 (70) (8 Supplement) LB-233; DOI: 10.1158/1538-7445.AM10-LB-233
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