title: Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Paoloni
authors.forename: Christina
authors.initials: C
authors.lastname: Mazcko
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Timothy
authors.initials: T
authors.lastname: Fan
authors.forename: Susan
authors.initials: S
authors.lastname: Lana
authors.forename: William
authors.initials: W
authors.lastname: Kisseberth
authors.forename: David M
authors.initials: DM
authors.lastname: Vail
authors.forename: Kaylee
authors.initials: K
authors.lastname: Nuckolls
authors.forename: Tanasa
authors.initials: T
authors.lastname: Osborne
authors.forename: Samuel
authors.initials: S
authors.lastname: Yalkowsy
authors.forename: Daniel
authors.initials: D
authors.lastname: Gustafson
authors.forename: Yunkai
authors.initials: Y
authors.lastname: Yu
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004283:Dog Diseases / Q000378:metabolism / Q000473:pathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007273:Injections, Intramuscular; D008297:Male; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus