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Introduction: Osteosarcoma (OS), the most common primary malignant bone tumor, is currently treated with pre- and postoperative chemotherapy in association with the surgical removal of the tumor. Conventional treatments allow to cure about 60 - 65% of patients with primary tumors and only 20 - 25% of patients with recurrent disease. New treatment approaches and drugs are therefore highly warranted to improve prognosis., Areas Covered: This review focuses on the therapeutic approaches that are under development or clinical evaluation in OS. Information was obtained from different and continuously updated data bases, as well as from literature searches, in which particular relevance was given to reports and reviews on new targeted therapies under clinical investigation in high-grade OS., Expert Opinion: OS is a heterogeneous tumor, with a great variability in treatment response between patients. It is therefore unlikely that a single therapeutic tool will be uniformly successful for all OS patients. This claims for the validation of new treatment approaches together with biologic/(pharmaco)genetic markers, which may select the most appropriate subgroup of patients for each treatment approach. Since some promising novel agents and treatment strategies are currently tested in Phase I/II/III clinical trials, we may hope that new therapies with superior efficacy and safety profiles will be identified in the next few years.

Background: Polo-like kinase 1 (PLK1) has emerged as a prognostic factor in various neoplasms, but only scarce data have been reported for high-grade osteosarcoma (OS). In this study, we assessed PLK1 expression and the efficacy of PLK1 inhibitor NMS-P937 in OS., Methods: PLK1 expression was assessed on 21 OS clinical samples and on a panel of human OS cell lines. In vitro efficacy of NMS-P937 was evaluated on nine drug-sensitive and six drug-resistant human OS cell lines, either as single agent or in combination with the drugs used in chemotherapy for OS., Results: PLK1 expression was higher in OS clinical samples and cell lines compared to normal human tissue. A higher PLK1 expression at diagnosis appeared to be associated with an unfavourable clinical outcome. PLK1 silencing produced growth inhibition, cell cycle retardation and apoptosis induction in human OS cell lines. NMS-P937 proved to be highly active in both drug-sensitive and drug-resistant cell lines, with the only exception of ABCB1-overexpressing, Doxorubicin (DX)-resistant variants. However, in these cells, the association of NMS-P937 with DX was able to revert DX-resistance by negatively interfering with ABCB1 transport activity. NMS-P937 was also able to decrease clonogenic and migration ability of human OS cell lines., Conclusion: PLK1 can be proposed as a new candidate target for OS. Targeting PLK1 in OS with NMS-P937 in association with conventional chemotherapeutic drugs may be a new interesting therapeutic option, since this approach has proved to be active against drug resistant cells.

Background: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours., Methods: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines., Results: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments., Conclusion: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.