Rapamycin increases neuroblastoma xenograft and host stromal derived osteoprotegerin inhibiting osteolytic bone disease in a bone metastasis model

• Published in: Journal of pediatric surgery Vol. 48; no. 1; pp. 47 - 55
• Main Authors: Hartwich, Joseph E, Orr, W. Shannon, Ng, Catherine Y, Spence, Yunyu, McLaughlin, Jillian M, Furman, Wayne L, McGregor, Lisa M, Davidoff, Andrew M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2013
• Subjects: Animals; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers - blood; Bone metastasis; Bone Neoplasms - blood; Bone Neoplasms - complications; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Fractures, Spontaneous - etiology; Fractures, Spontaneous - prevention & control; Humans; Injections, Intraperitoneal; Mice; Mice, SCID; Neuroblastoma; Neuroblastoma - blood; Neuroblastoma - complications; Neuroblastoma - drug therapy; Neuroblastoma - secondary; Osteoprotegerin; Osteoprotegerin - blood; Pediatrics; Rapamycin; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus - therapeutic use; Surgery; Treatment Outcome; Bone metastasis; Rapamycin; Neuroblastoma; Osteoprotegerin
• ISSN: 0022-3468; 1531-5037
• DOI: 10.1016/j.jpedsurg.2012.10.043

Abstract Purpose Osteoprotegerin (OPG) is a decoy receptor for the Receptor of NF-κB (RANK) ligand that can inhibit osteoclastogenesis. Previous studies have suggested that Mammalian Target of Rapamycin (mTOR) inhibition upregulates OPG production. We tested the hypothesis that the mTOR inhibitor rapamycin could inhibit neuroblastoma bone metastases through its action on OPG. Experimental Design An orthotopic model of bone metastasis was established. Mice with established disease were subsequently treated with rapamycin (5 mg/kg IP daily) or vehicle control (DMSO 1:1000). X-rays were obtained twice a week to detect pathologic fractures. Serum OPG levels were measured by ELISA after two weeks of treatment. Results Mice with bone disease receiving rapamycin had increased serum levels of OPG in the CHLA-20 mice compared to controls (36.89 pg/mL ± 3.90 vs 18.4 pg/mL ± 1.67, p = 0.004) and NB1691 tumor-bearing groups (46.03 ± 2.67 pg/mL vs 17.96 ± 1.84 pg/mL, p = 0.001), and a significantly longer median time to pathologic fractures with CHLA-20 (103 days vs 74.5 days, p = 0.014) and NB1691 xenografts. Conclusion In a xenograft model, increased OPG expression correlated with a delay to pathologic fracture suggesting a potential role for mTOR inhibitors in the treatment of neuroblastoma bone metastases.