title: Inhibition of chondrosarcoma growth by mTOR inhibitor in an in vivo syngeneic rat model.
abstract: BACKGROUND
  Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression.
  
  
  RESULTS
  Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence.
  
  
  CONCLUSIONS
  MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed.
authors: Department of Clinical Sciences, Centre de Recherche en Cancérologie UMR Inserm U1052-Equipe 11- CLB - Lyon, France.
authors: Jennifer
authors: J
authors: Perez
authors: Anne Valérie
authors: AV
authors: Decouvelaere
authors: Thomas
authors: T
authors: Pointecouteau
authors: Daniel
authors: D
authors: Pissaloux
authors: Jean Philippe
authors: JP
authors: Michot
authors: Anthony
authors: A
authors: Besse
authors: Jean Yves
authors: JY
authors: Blay
authors: Aurélie
authors: A
authors: Dutour
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D000068338:Everolimus; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D004317:Doxorubicin; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus