Related Experiment Video
Updated: Jun 12, 2026
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs
Melissa C Paoloni1, Christina Mazcko, Elizabeth Fox
1Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Background:
Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients.
Methodology/Principal Findings:
This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy.
Conclusions/Significance:
Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease.
Insights
Rapamycin is safe for dogs and modulates the mTOR pathway, supporting its use in canine cancer trials. This research informs the development of mTOR inhibitors for both canine and pediatric osteosarcoma patients.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- The mechanistic target of rapamycin (mTOR) pathway is crucial in cancer growth, progression, and chemoresistance.
- mTOR inhibitors are promising therapeutics, but require optimized dosing, regimens, and combination strategies.
- Canine osteosarcoma serves as a relevant model for studying mTOR inhibitors, potentially informing pediatric applications.
Purpose of the Study:
- To determine a safe, pharmacokinetically relevant, and pharmacodynamically active dose of parenteral rapamycin in dogs with appendicular osteosarcoma.
- To assess the modulation of the mTOR pathway in tumor tissue and peripheral blood mononuclear cells (PBMCs) following rapamycin administration.
- To evaluate the potential of dogs in the translational development of rapamycin and other mTOR inhibitors.
Main Methods:
- Prospective dose escalation study of intramuscular rapamycin in dogs with osteosarcoma.
- Collection of tumor biopsies and PBMCs pre-treatment and post-treatment.
- Pharmacokinetic sampling for whole blood rapamycin levels and trough concentrations.
- Assessment of mTOR pathway activity via pS6RP/S6RP and pAKT/AKT levels.
Main Results:
- No maximally tolerated dose of rapamycin was reached up to the highest tested dose (0.08 mg/kg).
- Rapamycin administration resulted in dose-dependent pharmacokinetic exposure.
- Modulation of the pS6RP/S6RP marker in both tumor tissue and PBMCs was observed across all dose cohorts.
- No significant change in pAKT/AKT levels was detected in tumor samples post-rapamycin therapy.
Conclusions:
- Rapamycin can be safely administered to dogs, achieving therapeutic exposures.
- The observed modulation of pS6RP/S6RP was not dose-dependent.
- Dogs represent a valuable model for the translational development of rapamycin and other mTOR inhibitors for cancer therapy.
- Further studies will define optimal rapamycin schedules and its role in minimal residual disease settings.
