Bone Abstracts

It has been established that disturbances of intracellular signaling pathways strongly contribute to the oncologic process. Indeed, phosphatidylinositol-3-kinase (PI3K) became a key target in cancer therapy, due to its high frequency of mutation and/or gain of function of its catalytic subunits in cancer cells. In this context, we investigated the in vitro and in vivo effects of a new PI3Kα inhibitor, BYL719 (Novartis Pharma), on bone cells and its therapeutic interest in osteosarcoma. In a first step, BYL719 effects have been assessed on osteoblastogenesis and osteoclastogenesis using human mesenchymal stem cells (hMSC) and human CD14⁺ monocytes respectively. These effects were further analyzed in vivo. In a second step, BYL719 activities in osteosarcoma cells were analyzed in vitro on proliferation, cell cycle and migration using murine (MOS-J and POS-1) and human (MG-63 and HOS) cell lines. The effect of BYL719 in osteosarcoma cells was finally investigated in vivo using the murine MOS-J osteoblastic osteosarcoma model through a follow-up of the tumor volume and an analysis of the bone microarchitecture. BYL719 strongly decreases the proliferation of hMCS in a dose-dependent manner and consequently reduces the mineralization process as revealed by alizarin red staining and qPCR analysis of osteoblastic genes. In parallel, BYL729 decreases osteoclastogenesis, reducing NFATc1 expression. Regarding tumor cells, BYL719 inhibits cell proliferation, effect characterized by a cell cycle arrest in G0/G1 phase, by an increase of cell death and associated with a marked decrease of cell migration. Western blot analysis of PI3K pathway confirmed the inhibition of mTOR/Akt pathway. In MOS-J osteosarcoma model, oral administration of BYL719 (50 mg/kg per day) results in a significant decrease of the tumor progression and of the tumor ectopic bone formation as confirmed by microCT. Overall, the present work demonstrates the therapeutic interest of a new orally administrated PI3Kα inhibitor (BYL719) as a neo-adjuvant in the therapeutic arsenal against osteosarcoma.