title: L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer.
abstract: Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients.
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Biteau
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guiho
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chatelais
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Taurelle
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chesneau
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France; Pediatric Oncology Unit, Hôpital Mère-EnfantNantes, F-44035, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Corradini
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR-957, Equipe Ligue Contre le Cancer 2012Nantes, F-44035, France; Université de Nantes, Faculté de Médecine, Laboratoire De Physiopathologie De La Résorption Osseuse Et Thérapie Des Tumeurs Osseuses PrimitivesNantes, F-44035, France; CHU Hôtel DieuNantes, F-44035, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
keywords: Osteosarcoma; bone protection; inhibition of lung metastases development; liposomal mifamurtide; zoledronic acid