Rapamycin increases neuroblastoma xenograft and host stromal derived osteoprotegerin inhibiting osteolytic bone disease in a bone metastasis model
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Published on: September 13, 2017
Joseph E Hartwich1, W Shannon Orr, Catherine Y Ng
1Department of Surgery, Virginia Commonwealth University, Richmond, VA 23284, USA.
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 (5mg/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 ± 1.84pg/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.
Insights
The mTOR inhibitor rapamycin increased osteoprotegerin (OPG) levels and delayed bone fractures in neuroblastoma bone metastasis models. This suggests rapamycin may be a potential treatment for neuroblastoma bone metastases.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Osteoprotegerin (OPG) inhibits osteoclastogenesis by acting as a decoy receptor for the Receptor of NF-κB (RANK) ligand.
- Mammalian Target of Rapamycin (mTOR) inhibition has been previously suggested to upregulate OPG production.
Purpose of the Study:
- To investigate the potential of the mTOR inhibitor rapamycin in treating neuroblastoma bone metastases.
- To test the hypothesis that rapamycin inhibits neuroblastoma bone metastases by modulating OPG levels.
Main Methods:
- An orthotopic mouse model of neuroblastoma bone metastasis was established.
- Mice received daily intraperitoneal injections of rapamycin (5mg/kg) or vehicle control.
- Pathologic fractures were monitored via X-ray, and serum OPG levels were measured by ELISA.
Main Results:
- Rapamycin treatment significantly increased serum OPG levels in mice bearing CHLA-20 and NB1691 neuroblastoma xenografts compared to controls.
- Mice treated with rapamycin exhibited a significantly longer median time to pathologic fractures in both xenograft models.
- Increased OPG levels positively correlated with delayed fracture incidence.
Conclusions:
- In a xenograft model, rapamycin administration led to increased OPG expression.
- This increase in OPG correlated with a delay in the development of pathologic fractures.
- These findings suggest a potential therapeutic role for mTOR inhibitors, such as rapamycin, in managing neuroblastoma bone metastases.
