IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical 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 Mínguez, Laia Cabellos, Judit Peix, Myron Schwartz, Vincenzo Mazzaferro, Jordi Bruix, Josep M. Llovet

Research output: Contribution to journalArticle

171 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)550-559
Number of pages10
JournalJournal of Hepatology
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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compound A 12
Hepatocellular Carcinoma
Loss of Heterozygosity
MicroRNAs
Heterografts
Dissection
Neoplasms
Cell Survival
Therapeutics
Down-Regulation
Monoclonal Antibodies
Cell Proliferation
Clinical Trials
Apoptosis
Gene Expression
Survival
Growth
Genes
Proteins
In Vitro Techniques

Keywords

  • A12
  • Hepatocellular carcinoma
  • IGF signaling
  • miR-100
  • Molecular therapy

ASJC Scopus subject areas

  • Hepatology

Cite this

IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. / Tovar, Victoria; Alsinet, Clara; Villanueva, Augusto; Hoshida, Yujin; Chiang, Derek Y.; Solé, Manel; Thung, Swan; Moyano, Susana; Toffanin, Sara; Mínguez, Beatriz; Cabellos, Laia; Peix, Judit; Schwartz, Myron; Mazzaferro, Vincenzo; Bruix, Jordi; Llovet, Josep M.

In: Journal of Hepatology, Vol. 52, No. 4, 01.04.2010, p. 550-559.

Research output: Contribution to journalArticle

Tovar, V, Alsinet, C, Villanueva, A, Hoshida, Y, Chiang, DY, Solé, M, Thung, S, Moyano, S, Toffanin, S, Mínguez, B, Cabellos, L, Peix, J, Schwartz, M, Mazzaferro, V, Bruix, J & Llovet, JM 2010, 'IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage', Journal of Hepatology, vol. 52, no. 4, pp. 550-559. https://doi.org/10.1016/j.jhep.2010.01.015
Tovar, Victoria ; Alsinet, Clara ; Villanueva, Augusto ; Hoshida, Yujin ; Chiang, Derek Y. ; Solé, Manel ; Thung, Swan ; Moyano, Susana ; Toffanin, Sara ; Mínguez, Beatriz ; Cabellos, Laia ; Peix, Judit ; Schwartz, Myron ; Mazzaferro, Vincenzo ; Bruix, Jordi ; Llovet, Josep M. / IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. In: Journal of Hepatology. 2010 ; Vol. 52, No. 4. pp. 550-559.
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AU - Tovar, Victoria

AU - Alsinet, Clara

AU - Villanueva, Augusto

AU - Hoshida, Yujin

AU - Chiang, Derek Y.

AU - Solé, Manel

AU - Thung, Swan

AU - Moyano, Susana

AU - Toffanin, Sara

AU - Mínguez, Beatriz

AU - Cabellos, Laia

AU - Peix, Judit

AU - Schwartz, Myron

AU - Mazzaferro, Vincenzo

AU - Bruix, Jordi

AU - Llovet, Josep M.

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N2 - 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.

AB - 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.

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