Bone Abstracts

Osteosarcoma is the most common primary malignant bone tumor, characterized by osteoid production and/or osteolytic lesions of bone. Despite recent improvements in chemotherapy and surgery, the problem of non-response to chemotherapy remains and constitutes a poor prognosis parameter. Consequently new therapeutic strategies aim to improve the overall rate of survival. The present work investigated the therapeutic interest of a dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor, NVP-BEZ235 (Novartis Pharma). This inhibitor targets both PI3K and mTOR kinase activity, in normal cells as in cells in which PI3K is mutated or PTEN is lost, two events frequently observed in oncologic process. In vitro effects of NVP-BEZ235 on proliferation, apoptosis and cell cycle have been assessed in five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mouse: MOS-J, POS-1). Moreover in vivo experiments have been performed to establish the in vivo effects of NVP-BEZ235 on osteosarcoma development. More precisely, the tumor volume and the bone microarchitecture have been analyzed in the murine MOS-J osteoblastic osteosarcoma model. The results showed that in vitro NVP-BEZ235 exerts a dose-dependent anti-proliferative effect and induces a cell cycle arrest in G0/G1 phase in all cell lines studied. However, the drug does not induce apoptosis of osteosarcoma cells. In the MOS-J osteosarcoma model, oral administration of NVP-BEZ235 (45 mg/kg per day) significantly inhibits the tumor development. Furthermore, NVP-BEZ235 reduces the tumor ectopic bone formation as shown by radiography and micro-CT. Overall, the present work demonstrates that the dual PI3K/mTOR inhibitor NVP-BEZ235 represents a promising drug in the therapeutic arsenal against osteosarcoma.