Association of mitogen activated protein kinase inhibitors with radiation therapy : focus on tumor oxygenation and multi-modal imaging markers of response to treatment

(eng) Hypoxia has emerged as an important factor in tumor biology and in the response to cancer treatment. Indeed, it is recognized that tumor hypoxia is a critical determinant for response to radiotherapy or chemotherapy. A particular area of interest is to combine radiotherapy with co-treatments that are able to increase tumor oxygenation at the time of irradiation. The first part of our work was focused on the effect of targeted therapies (MAPK inhibitors, i.e. Sorafenib, Gefitinib, and PD0325901) on tumor oxygenation and their resulting radiosensitizing properties. The rationale for combining MAPK inhibitors with radiation therapy was based on a previous study showing that FTI (RAS inhibitor) and Gefitinib (EGFR inhibitor) were able to decrease tumor hypoxia in experimental tumor models. Among mitogen-activated protein kinase (MAPK) pathways, the RAS/RAF/MEK/ERK pathway positively regulates tumor cell proliferation, differentiation, migration and confers resistance to apoptosis. The importance of the pathway is underscored by its constitutive activation in about 30% of cancers. This study constitutes the first demonstration of the tumor reoxygenation following administration of MAPK inhibitors that investigated potential mechanisms responsible for the reoxygenation effect and provides important insights for the sequence of administration of the treatments underlying the importance of individual monitoring of tumor oxygenation while combining treatments with radiation therapy. The predictive value of markers of response to treatment is of crucial importance in the management of cancer patients by allowing better individualization of treatment. In clinical setting, the prediction of tumor response to therapy is usually determined from measurements of tumor size evidenced by morphological imaging. However, with the increased use of targeted therapies, it has become clear that the standard anatomical methods of response evaluation are of limited value to assess the efficacy of these new treatment modalities because targeted therapy efficacy are no related to tumor shrinkage. Thus, development of different imaging modalities, i.e. magnetic resonance imaging/spectroscopy and positron emission tomography, to assess early tumor response to treatment, is needed. The second part of this thesis was therefore devoted to assess early markers of response to treatment with either Sorafenib in monotherapy or combined with radiation therapy, using molecular and functional imaging tools.