title: mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells In Vivo.
abstract: OBJECTIVE
  To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention.
  
  
  METHODS
  We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an antimetastatic therapeutic strategy through pharmacokinetic studies and preclinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis.
  
  
  RESULTS
  Metastatic osteosarcoma cells translate mRNA more efficiently than nonmetastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the MTDs defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents.
  
  
  CONCLUSIONS
  Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression, and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression. Clin Cancer Res; 22(24); 6129-41. ©2016 AACR.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio.|Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.|Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: James J
authors.initials: JJ
authors.lastname: Morrow
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Allyson
authors.initials: A
authors.lastname: Koyen
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lizardo
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Ling
authors.initials: L
authors.lastname: Ren
authors.affiliation: Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Waybright
authors.affiliation: Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado.|Pharmacology Shared Resource, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.affiliation: Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado.|Pharmacology Shared Resource, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.affiliation: Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, Illinois.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. ckhanna@ethosvet.com.
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus