Evaluation of the mTOT inhibitor, rapamycin in dogs with spontaneously derived osteosarcoma: A focus on preclinical pharmacokinetics and pharmacodynamics

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There is great interest in the development of mTOR inhibitors as anti-cancer therapies. mTOR functions as the nutrient sensor of the cell controlling protein translation, integral in cancer development and progression. The inhibition of mTOR is possible with Rapamycin, initially developed as an immunosuppressant for transplant patients, and novel analogues, known collectively as rapalogs. Although there are currently many treatment trials evaluating Rapamycin and rapalogs, the correlation of dose, pharmacodynamic modulation, response and benefit for these agents is poorly underestood. Furthermore, an understanding of optimal combinations of mTOR inhibitors with other cancer treatments is lacking. The complexity of questions related to the dose, exposure, dose-target, and benefit of a new cancer agent requires sophisticated and innovative model systems. Pet dogs that have naturally developed cancer may be such a model system. As such a preclinical dose escalation study in pet dogs with osteosarcoma was initiated to address questions of Rapamycin pharmacokinetics and its relationship to tumoral and PBMC correlative pharmacodynamics. This study was conducted through the Comparative Oncology Trials Consortium, a multi-institutional translational cancer therapy effort, led by the NCI, that integrates naturally occurring cancers seen in pet dogs into the development path of new cancer drugs. Dogs were administered paraenteral Rapamycin daily for an 8-day exposure starting at 0.01 mg/kg and finishing at 0.08 mg/kg. Biopsies were collected both pre and post treatment to assess mTOR pathway inhibition using modulation of 4EBP1 and S6K phosphorylation. Rapamycin was found to be safe and tolerable in tumor bearing dogs at doses relevant to typical human doses. There were two > grade 3 toxicities recorded but neither was attributable to the study drug. Hematologic and biochemical assessment was performed weekly for the 15-day study period and no significant toxicities reported. The tolerability of parenteral rapamycin in dogs will support the inclusion of dogs in future studies of mTOR inhibition. Pharmacokinetic and pharmacodynamic assessments are currently being performed. This study was designed as a necessary prequel for currently planned studies that will assess the activity of mTOR inhibition in osteosarcoma and future studies that will define optimal combinations of mTOR inhibition with both conventional and novel cancer treatments for sarcomas and other cancers.