Insulin-like Growth Factor 1 Receptor Axis Research Articles

Abstract A248: Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multitargeted inhibitors targeting insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor tyrosine kinases

Abstract Insulin-like growth factor-1 receptor (IGF1R) and members of ErbB family (eg. EGFR, ErbB2) are receptor tyrosine kianses that play significant roles in cancer and have been pursued as drug targets for cancer therapy. There is substantial evidence for the existence of reciprocal cross-talk between IGF1R axis and ErbB axis of cellular signaling. Acquired resistance to EGFR inhibitors gefitinib and erlotinib or ErbB2 inhibitor trastuzumab has been linked to activation of IGF1R signaling through induced overexpression of IGF1R or loss of IGF binding- proteins. Additionally, synergy between IGF1R inhibition and ErbB inhibition has been demonstrated in cancer cell growth inhibition and in xenograft models. Thus, molecules targeting both IGF1R and ErbB-family might have superior anti-tumor efficacy. This poster describes the lead discovery, optimization and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR and ErbB2. The leading compound, A-923573, showed IGF1R IC50 of 12 nM, EGFR (L858R) IC50 of 31 nM and ErbB2 IC50 of 11 nM, potent activity in cellular functional assays and anti-proliferation assays, as well as in an in vivo pharmacodynamic assay. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A248.

If Mammalian Target of Metformin Indirectly Is Mammalian Target of Rapamycin, Then the Insulin-Like Growth Factor-1 Receptor Axis Will Audit the Efficacy of Metformin in Cancer Clinical Trials

If Mammalian Target of Metformin Indirectly Is Mammalian Target of Rapamycin, Then the Insulin-Like Growth Factor-1 Receptor Axis Will Audit the Efficacy of Metformin in Cancer Clinical Trials

Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF‐1 receptor

IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously shown that h7C10, a humanized anti-IGF-1R Mab, exhibited potent antitumor activity in vivo. However, mechanisms of action of h7C10 are still unknown. Here, we showed that h7C10 inhibited IGF-1-induced IGF-1R phosphorylation in a dose-dependent manner. Also, h7C10 abolished IGF-1-induced activation of PI3K/AKT and MAPK pathways. Cell cycle progression and colony formation were affected in the presence of h7C10 probably because of the inhibition of IGF-1-induced cyclin D1 and E expression. In addition, we demonstrated that h7C10 induced a rapid IGF-1R internalization leading to an accumulation into cytoplasm resulting in receptor degradation. Using lysosome and proteasome inhibitors, we observed that the IGF-1R alpha- and beta-chains could follow different degradation routes. Thus, we demonstrated that antitumoral properties of h7C10 are the result of IGF-1-induced cell signaling inhibition and down-regulation of IGF-1R level suggesting that h7C10 could be a candidate for therapeutic applications.

EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells

The receptor tyrosine kinase (RTK) insulin like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis plays an important role in the development of hepatocellular carcinoma (HCC). EGCG inhibits activation of the various types of RTKs and that this is associated with inhibition of multiple downstream signaling pathways. In this study we examined the effects of EGCG on activity of the IGF/IGF-1R axis in HepG2 human HCC cells which express constitutive activation of this axis. The level of phosphorylated ( i.e. activated) form of the IGF-1R protein (p-IGF-1R) was increased in a series of human HCC cell lines when compared with the Hc normal human hepatocytes. EGCG preferentially inhibited growth of HepG2 cells when compared with Hc cells. Treatment of HepG2 cells with EGCG induced apoptosis and caused a decrease in the p-IGF-1R protein and its downstream signaling molecules including the p-ERK, p-Akt, p-Stat-3, and p-GSK-3β proteins, both in the absence or presence of ligand stimulation. EGCG also decreased the levels of both IGF-1 and IGF-2 proteins and mRNAs, but increased the levels of the IGFBP-3 protein. These findings suggest that EGCG can overcome the stimulatory effects of IGFs on the IGF-1R dependent signaling pathway, thus expanding the roles of EGCG as an inhibitor of critical RTKs involved in HCC cell proliferation. These results provide further evidence that EGCG may be useful in the chemoprevention or treatment of liver cancer.

Relation between Insulin-like growth factor-1 receptor (IGF-1R) expression and the efficacy of trastuzumab (T) monotherapy for hormone-resistant HER2-postitive metastatic breast cancer (MBC)

9578 Background: T is an active drug for HER2-positive MBC with excellent toxicity profile, but its anti-tumor effect as monotherapy is limited and the mechanism of T resistance is not elucidated. Lu Y et al. recently demonstrated in human breast cancer cell-lines that increased level of IGF-1R signaling adversely interferes with T's action on cell growth (JNCI, 2001). We assessed the predictive value of IGF-1R protein expression for T therapy in tumor samples using immunohistochemistry(IHC). Methods: Between June 2001 and May 2003, 39 patients without visceral crisis were treated with T monotherapy as the first line therapy for hormone-resistant MBC. All tumors were HER2 positive either by Herceptest(3+) or FISH. Among them, 26 formalin-fixed paraffin embedded tissue of primary or metastatic lesions were available. Mouse monoclonal antibody (clone 24–31) specific for alpha subunit was used for IGF-1R IHC. ER, PgR, IGF-BP3 was also evaluated by IHC. IGF-1R and IGFBP3 expression levels were measured from its staining on the membrane and cytoplasm, respectively, as mode-intensity (MI) by automated imaging analyzer(Ariol SL-50). T monotherapy was continued until clinical progression. Results: Median duration of T monotherapy was 78 days (range 20–375). The range of MI for IGF-1R and IGF-BP3 was 0–166.7 (mean 86.0, SD 40.8) and 0–86.4 (mean 57.3, SD 28.3), respectively. Neither IGF-1R MI nor IGF-BP3 MI correlated with duration of T monotherapy (p=.692 and .791, respectively). High IGF-1R MI (>50.0) was observed in 5 out of 6 patients who received T monotherapy more than 12 weeks without progression (1 CR, 5 MR), and 4 of the 5 patients showed high IGFBP3 MI(>50.0). Conclusions: In contrast to previously reported in vitro experiment, IGF-1R protein expression did not correlate with resistance to T monotherapy. Further studies are necessary to clarify the role of IGF-1R axis in mechanism of action of T. No significant financial relationships to disclose.