Targeting the IGF1 Pathway in Pediatric Sarcomas
We have previously demonstrated that IGFIR signaling plays a significant role in the growth and survival of pediatric sarcomas. We also showed that the survival signal provided by the IGFIR was in part mediated by activation of mTOR signaling, suggesting that combination therapy with IGFIR inhibition and mTOR inhibition may be advantageous. Preclinical studies using a human IGFIR moAb's confirmed the activity against rhabdomyosarcoma both in vitro and in vivo, however in vivo studies demonstrated that the growth inhibitory effect is transient. Ongoing studies are focused on identifying the mechanisms of resistance in vivo.
Subsequent clinical studies using a fully human IGFIR antibody demonstrated anti-tumor activity in Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma, although most responses were relatively short-lived. In summary, these data suggest that IGFIR blockade has activity against pediatric sarcomas, although resistance mechanisms develop and must be understood in order to fully realize the therapeutic potential of this approach in the clinic.