Igf-Ir Regulation Of Osteoclastogenesis In Neuroblastoma Bone Metastasis

Neuroblastoma is a tumor that is responsible for 15% of cancer deaths in children and has a mortality rate greater than 90% percent upon metastasis to bone. Due to the high mortality rate and lack of effective treatment options, our laboratory is investigating potential new therapeutic targets in neuroblastoma bone metastases. Since, insulin-like growth factor I (IGF-I) production in the bone promotes neuroblastoma growth and survival, our hypothesis is that inhibiting IGF-I receptor (IGF-IR) will prevent metastasis of this tumor to bone. Furthermore, neuroblastoma with increased IGF-IR expression induces osteoclasts to differentiate, with the percentage of differentiated osteoclasts in vitro increasing to 30% in the presence of conditioned medium from high IGF-IR expressing cells. The addition of a monoclonal, neutralizing antibody to the IGF-IR decreases the percentage of mature osteoclasts formed by over 50%. We are testing the hypothesis that IGF-IR activation in neuroblastoma alters the levels of RANK, RANKL and OPG, proteins involved in osteoclast differentiation. This alteration in RANK, RANKL, and OPG may cause osteoclast differentiation and osteolysis. Neuroblastoma cells with high IGF-IR protein levels express low levels of the decoy receptor OPG, while some lines also express high levels of RANKL. Therefore, we are currently testing the effect of IGF-IR inhibition on RANKL and OPG levels and subsequent effect on osteolysis. Citation Format: Chris A. Rivera-Pintado, Yufei Shan, Cynthia M. van Golen. IGF-IR regulation of osteoclastogenesis in neuroblastoma bone metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B39.