With modern polychemotherapy Ewing’s sarcoma exhibit remarkable chemosensitivity leading to 5-year survival rates approaching 60–70%. However, in the last decade, no significant progress has been achieved in terms of improved cure rates and quality of life. In addition, prognosis is poor either in relapsed patients and in patients with metastasis at diagnosis. Thus, it is imperative to develop novel therapeutic strategies and to identify markers for risk-adapted therapies.

The PROTHETS European Consortium through collaborative studies defined prognostic markers and new therapeutic targets in the Ewing’s sarcoma family of tumours (ESFT), to provide rigorous scientific justifications for the development of clinical trials for this rare disease. Genetic studies have been performed for the screening of high-risk patients and patients responding differently to chemotherapy.

Between others, these studies identified in gluthation metabolism a major pathway regulating Ewing’s sarcoma chemoresistance. The prognostic relevance of glutathione metabolism pathway was validated by RT-PCR and the expression of MGST1, the microsomal glutathione transferase (GST), was found to clearly predict EWS prognosis. MGST1 expression was associated with doxorubicin chemo sensitivity. This prompted to assess the in vitro effectiveness a new anticancer agent (NBDHEX) that efficiently inhibits GST enzymes..

The consortium have collected more than 600 cases in specific tissue arrays for validation studies. Their use allowed the identification of some markers of prognosis, either conventional or new (ki-67, adhesion proteins, GAL3BP). Overall, theses studies started to define possible forthcoming risk-adapted strategies.

Another goal of the project was the creation of new tools and drugs as well as the optimization of molecular approaches against three therapeutic targets, EWS-FLI1, CD99 and IGF-IR that have great potential in terms of clinical application. The studies on IGF-IR have provide the rationale for the currently on-going clinical studies in Ewing’s sarcoma.

In both Enchondromatosis (EC) and Multiple Osteochondromas (MO), multiple benign cartilaginous tumours occur, which have a severely increased risk of malignant progression. Preventing new tumor formation and malignant progression would benefit the prognosis of these patients. A protective effect of selective Cox-2 inhibitor celecoxib, has been suggested against development and growth of colorectal cancer in familial syndromes. At last year’s EMSOS meeting we reported on expression of Cox-2 in 37% (central) – 46% (peripheral) of conventional chondrosarcomas. mRNA levels of EC related tumours were slightly higher than the solitary tumours. Celecoxib treatment of the chondrosarcoma cell lines resulted in a 3 fold decrease of PGE2 levels already at 5 μM. A significant decrease in proliferation was found at 10 μM in OUMS27 and at 25 μM in SW1353 and CH2879 compared to DMSO controls.

For the present study we assessed the (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo using a xenograft model of immunoincompetent nude mice which were injected with cell line CH2879 subcutaneously. Tumour volume was measured during 8 weeks. Celecoxib serum levels were determined by HPLC. Expression of proliferation marker Ki-67 and Cox-2 was assessed by IHC.

Our in vivo results also showed a beneficial effect of high dose prophylactic celecoxib treatment. Tumour volumes were negatively correlated with celecoxib serum levels (r2=0.152). However, at the end of pubertal growth of the mice, a catch-up tumour growth was observed, resulting in the absence of differences in tumour volume between control and treatment groups. Accordingly, proliferation marker Ki67 was higher expressed in the treated groups at sacrifice.

This suggests that there is no role for celecoxib in the treatment of adult chondrosarcoma patients. Celecoxib treatment of younger patients, especially to prevent formation of new tumours in EC and OC patients, might be beneficial, however more research is necessary.