2007-2013 Fellowship in Oncology - Radiotherapy
2010-2011 Master 2 - Radiobiology
2011-2014 PhD Student
Glioblastoma is a challenge for antitumoral therapies. Glioblastoma, the most frequent and malignant brain tumor, is almost always rapidly fatal, with a median survival of only 14 month. It accounts for approximately 25% of all primary brain tumors. GBM patients are treated by surgery, radiotherapy and chemotherapy, however early tumor relapses occur within the irradiated volume due to a high resistance of glioblastoma cells to ionizing radiation. Treatment options for recurrent GBM are limited as most alternatives have already been explored: i.e. neurosurgery, full course of radiotherapy and chemotherapy. Optimal surgical resection might be possible in a subgroup of patients, however, it is accompanied by a high risk of morbidity due to the infiltrative nature of the tumor. Systemic chemotherapy might also offer modest benefit for a subgroup of patients (Rajan, 1994; Brandes,1996). For example, the most frequently offered alkylating drug, temozolomide, extends the median survival for only two month. Radiosurgery has been used to treat recurrent glioblastoma with limited success (four month increase of mean survival) mainly ascribed to the extreme radio-resistance of GBM cells. Since radio-resistance is often the result of elevated DNA repair capacity, we propose to investigate the role of DNA repair pathways in this resistance and to prospect the potential sensitization of glioma by a new generation of repair inhibitors developed in the laboratory.
Rationale for using DNA repair inhibitors in GBM treatment. Two recent works have demonstrated
: i) the link between the activation of PI3K/Akt pathway (previously described as a poor prognostics (Chakravarti et al., 2004)), repair of DNA damage and radioresistance (Kao et al., 2006); and ii) the contribution of glioma stem cells to radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity (Bao et al., 2006).
The siDNA strategy to inhibit DNA repair. Our laboratory has developed a new strategy to inhibit the major DNA repair pathways, by baiting and hijacking the enzyme complexes that repair DNA, diverting them away from their physiologic target, the DSBs induced by irradiation on chromosomes. Dbait molecules that mimic double-strand breaks, trap the DNA dependent kinase complex (DNA-PK) activating its kinase activity and prevent repair proteins to form foci at the damage site on chromosomes, compromising the ability of cancer cells to survive to treatment.
The project will focus on demonstrating the efficacy of the association of Dbait to radiotherapy for treating GBM and characterizing the patient population that could benefit of this treatment. For this purpose 12 different models with subcutaneous or orthotopic xenografted human tumors have been developed in our laboratory. They will be used to assay various protocols of treatment association using systemic or local delivery of Dbait. The sensitivity of the different models to the combined treatment of radiotherapy and Dbait will be determined. The expression and posttranslational modifications of the main proteins of the DNA damage repair pathways will be analyzed in the xenografted tumors and modelled to predict the sensitivity to treatment. This part will be performed using the reversed-phase protein array (RPPA) technology and bioinformatics maps we have already validated. At least 64 proteins of the DNA damage signaling pathways can be analyzed on more than 200 tumor samples simultaneously.
A similar RPPA study
, will be performed using surgical samples of GBM collected with patient consent, to determine how frequent in the population are the DNA repair defect we have observed to be associated to sensitivity to Dbait in the xenografted models and to correlate DNA repair capacity to treatment outcome.
The project will be conducted both in the laboratory of Dr. Marie Dutreix (research center, Institut Curie) and in the group of Prof. Pierre Verrelle (department of radiotherapy, J. Perrin hospital, Clermont-Ferrand) under the supervision of both Marie Dutreix and Pierre Verrelle.