Determination of the telomeric status as a radiotherapy response predictive marker in Glioma

The full text of the publication follows. Gliomas are the most common primary brain tumors with 2,250 cases diagnosed each year in France. Glioblastoma, the most advanced stage (stage IV) of glioma, is associated with a median overall survival inferior to 1 year, even after a combined treatment with surgery and radiotherapy. Both the difficulty of total tumor resection and the tumor radioresistance are responsible for local recurrence causing the death of patients. It is therefore necessary to develop innovative strategies to potentiate the effect of radiation therapy or to replace them. A new type of radiation - Carbon ion radiotherapy (12C) - demonstrates an excellent ballistic and a two fold higher biological effect compared with photon. This treatment will be soon available in France to treat radioresistant tumors. Thus it becomes necessary to identify radioresistance predictive markers in glioma to prescribe such therapy. The telomere status - telomere size (TT) and telomerase activity (TA) - modulates sensitivity to conventional radiotherapy in vitro and in vivo in various tumor types. We propose to determine if the TT and/or the TA could be radioresistance predictive markers and if theses parameters influence cell response to carbon therapy. To do this, we established stable cell lines over-expressing hTERT (the telomerase catalytic subunit) at different levels (Telo0, Telo+ and Telo++).We have obtained in a same genetic background (line U373MG), different TT and TA. We observed a positive correlation between the TT on the one hand and radioresistance (p<0.05) and also the TA and radioresistance (p<0.05). This correlation disappeared during carbon irradiation. Thus the telomere status determines the response to photon radiation but not to carbon hadron-therapy. These results support the in vitro evaluation of the TT or TA as predictive markers of response to conventional radiotherapy, which would steer patients to hadron-therapy using carbon ions. (authors)