title: NVP-BEZ235 as a new therapeutic option for sarcomas.
abstract: OBJECTIVE
  To evaluate the in vitro and in vivo effects of NVP-BEZ235, a dual pan-phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor in the three most common musculoskeletal tumors (osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma).
  
  
  METHODS
  Antiproliferative activity as well as the effects on migration and metastasis were evaluated in a panel of osteosarcoma, Ewing's sarcoma, as well as rhabdomyosarcoma cell lines. Moreover, simultaneous and sequential treatments were done in association with two of the most important conventional drugs in the treatment of sarcoma, doxorubicin and vincristine.
  
  
  RESULTS
  NVPBEZ235 effectively blocked the pathway in in vitro and in vivo settings. Under the experimental conditions tested, the compound induced disease stasis, by arresting cells in G(1) phase of cell cycle, without remarkable effects on apoptosis. As a consequence, to obtain the maximum exploitation of its therapeutic potential, NVP-BEZ235 has been evaluated in combination with conventional cytotoxic agents, thus showing promising efficacy with either doxorubicin and vincristine. Inhibition of the phosphoinositide 3-kinase/mammalian target of rapamycin pathway increased activation of extracellular signal-regulated kinase 1/2, likely due to the presence of autocrine circuits shifting growth factor signaling toward the mitogen-activated protein kinase pathway. This supports the combined use of NVP-BEZ235 with other small signaling inhibitors. Here, we showed synergistic effects when the compound was associated with a anti-insulin-like growth factor-I receptor tyrosine kinase inhibitor. NVP-BEZ235 also inhibited cell migration and metastasis. Combination with vincristine further potentiated the antimetastatic effects.
  
  
  CONCLUSIONS
  NVP-BEZ235 displays the features to be considered for sarcoma therapy to potentiate the activity of other anticancer agents. The drug is currently undergoing phase I/II clinical trials in advanced cancer patients.
authors.affiliation: Laboratorio di Ricerca Oncologica, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Manara
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.forename: Diana
authors.initials: D
authors.lastname: Zambelli
authors.forename: Selena
authors.initials: S
authors.lastname: Ventura
authors.forename: Clara
authors.initials: C
authors.lastname: Guerzoni
authors.forename: Lorena
authors.initials: L
authors.lastname: Landuzzi
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Saveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Mario
authors.initials: M
authors.lastname: Mercuri
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D019042:Muscle Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; C531198:dactolisib