The preclinical model used in this study reproduces thus clinical situations in large chondrosarcoma. This suggests that everolimus could be worth exploring as adjuvant treatment at least in patients with grade 2 or higher chondrosarcoma. Whether everolimus would be able to show the same antitumor activity in all chondrosarcoma subtypes will be tested in a prospective randomized trial scheduled to be activated in 2012 in the French Sarcoma Group. Although everolimus as monotherapy showed a strong antitumor effect and did not induce an increase in phosphorilated Akt in our chondrosarcoma model one cannot put aside the possibility that resistance could emerge in response to long term mTORC1 inhibition.ItisknownthatblockadeofmTORsignalingbyrapalogs leads to loss of ABT-199 feedback inhibition on Akt. That could potentially result in increased cell survival and resistance to cancer therapy. To prevent such resistance mechanism and additionally improve everolimus therapeutic efficiency everolimus-based combination therapy could 
be envisionned. Such dual targeted approaches targeting mTOR and Akt, or mTOR and PI3K have proven to be pertinent in preclinical models and one has reached the clinical phase in patients with advanced sarcomas and other solid tumors. Another possible combination could be to add a bone remodelling agent to everolimus. Indeed, the combination of zoledronate to everolimus was effective in inhibiting tumor progression and in protecting bone in murine osteosarcoma model. The latter effect being the result of zoledronate rather than the one of everolimus. Like osteosarcoma, chondrosarcoma is characterized by a tumor-induced osteolysis; moreover, zoledronate has already proven to be an efficient agent in the same chondrosarcoma model. Thus it seems pertinent to hypothesize that the combination of everolimus to zoledronate could be efficient in this tumor. Such combined therapies are worth exploring in preclinical settings. In conclusion, the present results show that everolimus would be an effective antitumor agent in chondrosarcoma. Besides, the inhibition of tumor regrowth following surgery suggests that everolimus could be used as adjuvant long-term therapy in chondrosarcoma patients following surgery. These results open the way to new therapeutic approaches and led to a prospective phase II clinical trial initiatied in the French Sarcoma Group. After infection of the host cell and liberation of the RNA genome from the protecting virus particle, the viral RNA is translated into a multi-domain polyprotein that is proteolytically cleaved into ten products. The structural proteins are then used to assemble new virus particles, while the non-structural proteins participate in the replication of the viral genome. In the course of RNA replication, the viral genome is used as a template for the synthesis of negative-strand RNA, which next acts as a template for the production of positive-strand RNA. Replication is catalyzed by the NS3 helicase and the NS5B RNA-dependent RNA polymerase. The helicase represents the C-terminal portion of the NS3 protein. The NS3 helicase unwinds in an ATP-dependent manner doublestranded RNA into single strands. The shallow active site groove allows minor structural modifications to interfere with substrate binding, promoting resistance. Because NS5B, the RNA-dependent RNA polymerase, misincorporates bases at a high rate, HCV constantly mutates as it replicates. The process of constant mutation leads to heterogeneous viral populations and multiple quasispecies of HCV in Z-VAD-FMK infected patients. Mutations in the viral genome cause a rapid emergence of HCV genotypes which resist therapeutic intervention and help the virus to evade.