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.
Procedure: 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.