Characterization of chemotherapy-induced cell death in glioblastoma

Glioblastoma constitute the most frequent and deadliest type of brain tumors. Their annual incidence is estimated between 5 and 8 cases per 100,000 people in Europe and North America. They are resistant to all current therapies and are associated with a very high rate of recurrence. The associated prognosis is generally very poor and most patients die within a year after diagnosis. Unfortunately, despite extensive research and use of multimodality treatments combining surgical resection, chemotherapy and radiotherapy, survival hasn’t really much improved over the last 20 years. Indeed, these tumors were shown to be characterized by a high radio- and chemo-resistance. Glioblastoma cells exhibit overexpression of the anti-apoptotic Bcl-2 family proteins and downregulation of its pro-apoptotic members, high expression of the IAPs (Inhibitors of Apoptosis Proteins) and constitutive activation of the pro-survival NF-κB pathway. Currently, the most commonly used treatment offering the best prognosis to patients consists in a combination of maximal surgical tumor resection (when feasible) with subsequent radio- and/or chemotherapy. Among the most commonly used chemotherapeutic agents, the alkylating agent temozolomide and the topoisomerase I inhibitor camptothecin occupy a central position. Therefore, in this study, the impact of both temozolomide and irinotecan (a soluble derivative of camptothecin) on glioma cell survival will be investigated. Important progress was made in the comprehension of the molecular mechanisms underlying tumor development and progression however, survival benefits conferred by the use of new drugs and therapeutic strategies are counted in months rather than years. Consequently, there is an urge to rapidly improve the efficiency of the currently used treatments. This research project consists in (i) the study of the mechanisms implicated in glioblastoma cell death induced by two chemotherapeutic agents : temozolomide and irinotecan, (ii) the identification of the mechanisms underlying the resistance of glioblastoma to these treatments, (iii) the use of pharmacological tools to interfere with those resistance strategies to enhance chemotherapy efficiency. Necrosis was, until recently, long thought to be only accidental. However, it was shown to be finely regulated by specific signalling pathways. Programmed necrosis often takes place in cells in which apoptosis cannot be properly activated and serves as a back-up cell death pathway. Previous work from our lab having already demonstrated that glioblastoma are, at least partially, apoptosis-defective, special emphasis is put on the study of necrotic parameters. Results from survival tests performed on several glioblastoma cell lines in the presence of necrotic inhibitors like necrostatin-1 (an inhibitor of the central regulator of the necrotic pathway RIP1) allows to partially overcome temozolomide and irinotecan-induced glioblastoma cell death, highlighting the role played by programmed necrosis in chemotherapy sensitivity