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 vivoA12 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.

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

“…Our preclinical studies have identified measurable pharmacodynamic endpoints such as serum IGF bioactivity that will be useful for defining the pharmacokinetic/pharmacodynamic (PK/PD) relationship in humans. With regards to rational rather than arbitrary drug combinations, our findings indicate that coadministration of BI 836845 with rapalogs deserves consideration, and with respect to potential selection criteria for tumors that may be particularly responsive, autocrine expression of IGF-I or IGF-II may define a subpopulation of interest (52).…”

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…In vitro studies showed that abrogation of IGF1R activation and downstream signaling by the monoclonal antibody A12 significantly decreased cell viability and proliferation 1414. Although several IGF1R inhibitors or blocking antibodies have been tested in preclinical models or clinical trials for patients with HCC,9, 14, 15, 16 none has been approved by the FDA, possibly because inhibition of IGF1R alone may not be sufficient to effectively inhibit HCC cell growth and survival.…”

“…In vivo , A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis 14. Although several IGF1R inhibitors or blocking antibodies have been tested in preclinical models or clinical trials for patients with HCC,9, 14, 15, 16 none has been approved by the FDA, possibly because inhibition of IGF1R alone may not be sufficient to effectively inhibit HCC cell growth and survival. Our data support this hypothesis as inhibition of IGF1R by shRNA or ceritinib has only a modest suppression on HCC proliferation and survival (Figs.…”

“…Overexpression of IGF1R was detected in 33% of human HCCs, and increased activation of IGF1R was observed in 52% of HCC tumors 13. Abrogation of IGF1R activation significantly but modestly decreases HCC cell viability and proliferation 14. Although several IGF1R inhibitors have been tested in clinical trials,9, 15, 16 none have been approved by the U.S. Food and Drug Administration (FDA).…”

Whole-exome sequencing identifies mutated PCK2 and HUWE1 associated with carcinoma cell proliferation in a hepatocellular carcinoma patient

“…In addition, reduced expression of IGFBP-3 associated with promoter hypermethylation has been reported in human HCC samples (21). A recent study found aberrant activation of IGF1R in 21% of early stage hepatitis C-related HCC xases, and provided preclinical evidence of antineoplastic activity following IGF1R selective blockade using a monoclonal antibody (22). The potential role of the HBx viral protein as an inducer of IGF-IR expression has also been suggested (23).…”