title: IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma.
abstract: BACKGROUND
  High-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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  OSI-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.
  
  
  CONCLUSIONS
  This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2300RC, the Netherlands.
authors.forename: Marieke L
authors.initials: ML
authors.lastname: Kuijjer
authors.forename: Elisabeth F P
authors.initials: EF
authors.lastname: Peterse
authors.forename: Brendy E W M
authors.initials: BE
authors.lastname: van den Akker
authors.forename: Inge H
authors.initials: IH
authors.lastname: Briaire-de Bruijn
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Meza-Zepeda
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.forename: A Bassim
authors.initials: AB
authors.lastname: Hassan
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
mesh_terms: D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D060787:Neoplasm Grading; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D011972:Receptor, Insulin / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D011719:Pyrazines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin