title: R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts.
abstract: BACKGROUND
  The combination of rapamycin and R1507, a fully human IgG1 monoclonal antibody targeting the IGF-1 receptor (IGF-1R), in osteosarcoma xenograft tumors in vivo is evaluated in this report.
  
  
  METHODS
  Six osteosarcoma xenograft tumor models were evaluated for growth inhibition after monotherapy with R1507, rapamycin, and the combination of both drugs. Phosphorylation of proteins involved in IGF-1R signaling is evaluated at various time points by immunoblotting.
  
  
  RESULTS
  IGF-1R was expressed in five of the six human osteosarcoma tumor lines. Objective responses to R1507 were seen in four of the six tumor lines (OS1, OS2, OS9, and OS17) including one complete response in OS1. IGF-1R protein levels did not predict degree of response to R1507 in the sensitive tumors. However, in one of the two R1507-resistant tumors (OS33), there was a minimal expression of IGF-1R. An increase in AKT phosphorylation was observed in all the osteosarcoma tumors treated with rapamycin. However, phosphorylation of AKT was inhibited when rapamycin was used in combination with R1507. In three of the xenograft tumor lines, there was an improvement in response when R1507 was used in combination with rapamycin.
  
  
  CONCLUSIONS
  IGF-1R inhibition by R1507 induced tumor growth delays and improvement in event-free survival in four of six osteosarcoma xenograft tumor lines. R1507 negates increased signaling through AKT in response to mammalian target of rapamycin inhibition, suggesting that the combination is worthy of further evaluation in patients. As R1507 and other IGF-1R inhibitors advance in clinical trials, it will be important to understand biomarkers of response and pathways of resistance.
authors.affiliation: Division of Hematology and Oncology, Alfred I. duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, Delaware 19803, USA. eakolb@nemours.org
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Davida
authors.initials: D
authors.lastname: Kamara
authors.forename: Wendong
authors.initials: W
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.forename: Pooja
authors.initials: P
authors.lastname: Hingorani
authors.forename: Laurence
authors.initials: L
authors.lastname: Baker
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1; D020123:Sirolimus