Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing’s sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the ‘seed and soil theory’. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells.
Current treatment of malignant primary bone tumours consists of excision of the tumour, associated with high toxicity chemotherapy. Unfortunately, in many cases, an absence of response to anti-tumour drugs is observed, leading to the development of metastases and the death of the patient. Survival is closely correlated to the response of tumour cells to anti-mitotic drugs, reaching 70% in 5 years for osteosarcomas in the best series and only 30% when the pulmonary metastases are detected at the time of diagnosis. Ewing’s sarcomas also give a poor prognosis in their metastatic form. In fact, the prognosis of patients with bone or medullary metastases and that of patients who relapse is very poor and <25% of them are cured. Tumours found at the time of diagnosis but that resist to initial chemotherapy also give a poor prognosis. Whether the main cause of most bone sarcomas are unknown, the close relationship between tumours cells and their local microenvironment strongly contributes to their survival and proliferation.
Most of the signalling pathways are implicated in cell proliferation and apoptosis resistance. They are mediated by proteins with kinase activity, both outside (at the cell membrane) or inside the cells (cytoplasm or nucleus). These proteins may be inhibited by monoclonal antibodies directed against extra-membrane receptor or small molecule inhibitors of the intracellular kinase domain (
The insulin-like growth factor-1 receptor (IGF1-R) pathway has an important role in osteosarcoma and Ewing’s sarcoma.
mTOR being a downstream pathway activated by IGF-1 binding to its receptor IGF1-R, its targeting has been also largely studied. The mTOR inhibitor rapamycin was first used in children to prevent graft rejection. mTOR, an intra-cytoplasmic serine kinase regulated by AKT has been envisaged to treat osteosarcoma.
As several signalling pathways are activated during tumour growth, the development of drugs that have several targets (mostly with kinase activity) has recently emerged in many types of cancers, including osteosarcoma and Ewing’s sarcoma (
High expression of c-KIT (stem cell factor receptor) and platelet-derived growth factor receptor (PDGFR) is observed in Ewing’s sarcoma and osteosarcoma
Dasatinib shows in vitro cytostatic and anti-migration effect and no apoptosis in Ewing’s sarcoma.
In osteosarcoma, sorafenib inhibits tumour growth, angiogenesis (by VEGF inhibition), invasion (by MMP2 inhibition) and pulmonary metastases formation (via inhibition of the Ezrin/β4-integrin/PI3K signalling pathway), and induced apoptosis.
Efficacy was observed in in vivo models of most paediatric tumours, including 4/5 Ewing’s sarcoma xenografts.
Pazopanib appeared active in paediatric in vivo tumour models, used as single agent in Ewing’s sarcoma
The CDK (cyclin-dependent kinase) inhibitor dinaciclib induces in vitro osteosarcoma cell apoptosis.
Resistance to apoptosis is a key element in tumour progression and chemoresistance. The mechanisms involved increased survival signals (growth factors/TK receptors, downstream pathways), anti-apoptotic molecule overexpression (Bcl-2, Bcl-XL and FAK in osteosarcoma), pro-apoptotic molecule under expression (Bim in osteosarcoma), or resistance to cell death receptors Fas/FasL (Fas ligand) or TRAIL (TNF-related apoptosis-inducing ligand) (
Autophagy, a cell survival program implicated in tumourogenesis and chemoresistance,
Hedgehog signalling pathway has an important role in growing organisms (embryogenesis, morphogenesis) and is activated in osteosarcoma and Ewing’s sarcoma (GLI is a EWS–FLI1 target).
HDAC and histone acetyl transferase (HAT) are enzymes that catalyse histone deacetylation and acetylation, respectively, modifying chromatin access to transcription factors and gene transcription. Two paediatric phases I trials have been completed with two HDAC inhibitors (vorinostat and valproic acid).
HSP90 is a chaperone protein implicated in numerous cancers, overexpressed in 21/54 Ewing’s sarcoma patient samples.
c-Met belongs to the receptor tyrosine kinases and is strongly involved in the control of mitosis, cell motility and cell survival and consequently alterations (overexpression, mutation and so on) of c-Met signalling induced by its ligand, the hepatocyte growth factor lead to the proliferation, invasiveness and metastasis of numerous cancer cell types including osteosarcoma. hepatocyte growth factor receptor/c-Met has been shown to be overexpressed and activated in osteosarcoma cells.
The multiplicity of targets in primitive malignant bone tumours of children and adolescents and the experience with anti-IGF1-R antibodies suggest that therapeutic future in these tumours will reside in the way of combining these therapies targeting different characteristics of the malignant cells and their environment. The development of therapies targeting founder genetic abnormalities such as EWS-FLI in EW appears crucial. More efforts remain necessary to understand biological processes implicated in osteosarcoma oncogenesis. An increasing number of new molecular therapies becoming available and the rarity of these tumours also require developing relevant preclinical models and new methodologies for therapeutic trials.
Targeting of signalling pathways. Tyrosine kinase receptors (IGF1-R (right panel) and others such as VEGFR, PDGFR, c-MET and so on (left panel)) are activated upon binding of their respective ligands to their extracellular domain. It subsequently leads to activation of various signalling pathways (PI3K/Akt/mTOR, Ras/RAF/MEK and so on) promoting malignancies. In red, are mentioned the main therapies based on targeting of tyrosine kinase proteins and on associated downstream signalling pathways. Multi-target inhibitors has been also developed (dual PI3K/mTOR, dual mTOR/DNA-PK, dasatinib and so on).
Targeting of key factors associated to cell cycle, cell death resistance, autophagy and other metabolic activities. Genomic, transcriptional and functional analyses carried out on bone sarcoma cells identified numerous targets, which constitute the basis for the development of sophisticated and promising therapies (in red). These targets are involved in the key mechanisms controlling cell biology (cell cycle, apoptosis, replicative immortality, autophagy, histone deacetylation and acetylation, and so on).