Valutazione dell'effetto antitumorale di Cabozantinib sull'osteosarcoma e sul microambiente osseo

Osteosarcoma (OS) is the most common primary malignant tumor of bone. Thanks to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to current standard treatments and for this reason, novel therapies are needed. Literature data assert that c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. In the present study, we aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ on in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. We demonstrated that CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signalling pathways. As a consequence, OS cells activate autophagic process. Furthermore, CBZ leads to a further inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor ?B (RANK), thanks to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.