NVP-BEZ235 as a new therapeutic option for sarcomas.
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.
Manara
Maria C
MC
Laboratorio di Ricerca Oncologica, Istituto Ortopedico Rizzoli, Bologna, Italy.
Nicoletti
Giordano
G
Zambelli
Diana
D
Ventura
Selena
S
Guerzoni
Clara
C
Landuzzi
Lorena
L
Lollini
Pier-Luigi
PL
Maira
Saveur-Michel
SM
García-Echeverría
Carlos
C
Mercuri
Mario
M
Picci
Piero
P
Scotlandi
Katia
K
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
D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; C531198:dactolisib