IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma

Abstract

BackgroundHigh-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment.MethodsWe performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma – mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays.ResultsOSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines.ConclusionsThis study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma.

Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-β as Involved in the Pathogenesis of Osteosarcoma

“…Simultaneous loss of all the IGFBPs and IGFBPrPs in osteosarcoma compared with normal bone cells is striking. This was similarly found in a study using comparable methods [12]. Cells may obtain self-sufficiency by maintaining IGF-1 activity through downregulation of the IGFBPs.…”

“…Cells may obtain self-sufficiency by maintaining IGF-1 activity through downregulation of the IGFBPs. This might provide new targets for therapy for this disease [12].…”

Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

“…From a clinical point of view, increased expression of IGF1R in response to in vitro and in vivo exposure to trabectedin, provides the rationale for a combined use of trabectedin with anti-IGF1R agents. Here, we demonstrate the advantages of this combination either using HAb AVE1642, a well-tolerated agent that binds human IGF1R specifically and with high affinity (45,46), or the dual inhibitor IGF1R/IR, OSI-906, a small molecule shown to have antitumoral activity against several tumors (47,48), including osteosarcoma (49). The association of OSI-906 with trabectedin gave synergistic effects in all of the 13 EWS cell lines here considered, including cells resistant to trabectedin (18) or to anti-IGF1R agents (29).…”

Effect of hypoxia on the expression of genes that encode some IGFBP and CCN proteins in U87 glioma cells depends on IRE1 signaling

“…It is well known that insulin-like growth factors and the signal transduction networks play important roles in tumorigenesis and metastasis as well as in metabolic diseases [1,2]. IGFBPs participate in endoplasmic reticulum stress, which is an important factor of tumor growth, insulin resistance, and obesity [3][4][5]. It is interesting to note that there is the cross talk between IGF and insulin receptor signaling pathways at the receptor level or at downstream signaling level.…”