ED Sciences de la Vie et de la Santé
Metabolic adaptations sustaining glioblastoma development and relapse - Study of the role of lactate metabolism
by Claire LARRIEU (Institut de Biochimie et Génétique Cellulaires)
The defense will take place at 14h00 - Salle de conférence IBGC, Institut de Biochimie et Génétique Cellulaires (IBGC), CNRS UMR 5095, 1 rue Camille Saint-Saëns, CS 61390, 33077 Bordeaux cedex
in front of the jury composed of
- Thomas DAUBON - Directeur de recherche - IBGC CNRS UMR5095 - Université de Bordeaux - Directeur de these
- Marie-Pierre JUNIER - Directrice de recherche - IPBS / Campus Pierre et Marie Curie - Rapporteur
- Anthony LEMARIE - Maître de conférences - Toulouse Cancer Research Center CRCT - Inserm UMR1037 - Rapporteur
- Luc PELLERIN - Professeur des universités - IFR BioSanté - Inserm U1313 IRMETIST - Université de Poitiers - Examinateur
- Hélène CASTEL - Directrice de recherche - Inserm U1239, Institute of Biomedical Research and Innovation (IRIB) - University of Rouen Normandie - Examinateur
Glioblastoma (GB) is the most frequent and most aggressive brain cancer in adult. Additionally to strong proliferative and infiltrative capacities responsible for bad prognosis and frequent relapse, GB cells also exhibit high metabolic plasticity. In fact, glycolytic and oxidative cells live side by side in the tumor and form a metabolic symbiosis supporting survival, progression and resistance to treatment of these malignant cells. Our work show that this intra-tumoral metabolic symbiosis in GB is centered on lactate exchanges between the core tumor and the invasive population spreading in the brain. Disturbing this intra-tumoral lactate metabolism, directly by blocking LDHs or indirectly by targeting regulatory enzymes such as PDHKs, has shown interesting alteration of GB progression in vitro and in vivo. In clinic, surgical resection of the tumor (when possible) is often the first step of therapy for patients with GB. Traumatic and invasive act for patients, resection is also traumatic for the tumor itself, by strongly disturbing intra-tumoral metabolic symbiosis. However, invasive cells escaping this surgical step are invariably switching back to a proliferative phenotype and growing a new tumor. Indeed, surgical removal of tumor mass, the main glycolytic producer of lactate in GB, induces lactate fluctuations also in these post-resection residual GB cells. These fluctuations seem to be responsible for metabolic rewiring sustaining survival and proliferation. Then, adding a metabolic block to the actual standard therapy could be of significant interest to prevent GB progression and relapse.
ED Sciences Physiques et de l'Ingénieur
Dosimetry of alpha-emitting radionuclides for targeted radionuclide therapy
by Alexandre LAROUZE (Centre Lasers Intenses et Applications)
The defense will take place at 14h00 - Université de Bordeaux Université de Bordeaux 351 Cours de la Libération 33405 Talence cedex
in front of the jury composed of
- Christophe CHAMPION - Professeur - Université de Bordeaux - Directeur de these
- Emily LAMOUR - Professeure des universités - Université Paris Sorbonne - Rapporteur
- Régine GSCHWIND - Professeure des universités - Université de Franche-Comté - Rapporteur
- Jean-Emmanuel GROETZ - Maître de conférences - Université de Franche-Comté - Examinateur
- Laurence BORDENAVE - Professeure émérite - Université de Bordeaux - Examinateur
- Juan Manuel MONTI - Professeur adjoint - Universidad Nacional de Rosario - Examinateur
- Thanh-Ha NGUYEN-BUI - Directrice de recherche - Université de Bordeaux - Examinateur
- Elif HINDIE - Professeur des universités - praticien hospitalier - Université de Bordeaux - CoDirecteur de these
Targeted radionuclide therapy (TRT) is a nuclear medicine-based cancer treatment technique that consists in coupling a radionuclide with a carrier molecule able to specifically target cancer cells. In this context, the radionuclides commonly used in clinic are mainly β− emitters (177Lu, 131I, 90Y), although an α-emitter (223Ra) has been recently approved for the treatment of prostate cancer. The current doctoral thesis aims at characterizing the radio-induced energy deposits of the most promising α-emitters for TRT by means of a numerical approach based on a homemade Monte Carlo track structure code named TILDA-V. As part of this thesis, the transport of α-particles in the biological environment was refined by the development of new theoretical models implemented into TILDA-V. The numerical predictions also obtained in terms of range, stopping power, dose profiles were compared with experiments as well as theoretical data provided by existing simulation codes. In most cases, an excellent agreement was observed. Besides, a complete dosimetric study of α-emitters, including isolated single cell targets and/or cell clusters, was provided and compared with other existing predictions. In this context, the therapeutic potential of α-emitters was compared with that of β−-emitters previously studied with TILDA-V. Finally, the TILDA-V code was also extended to the modeling of radiation-induced DNA damages by implementing the cross sections of all the interactions induced by Heq+ ions on DNA components. In this work, the most promising α-emitters for TRT were characterized on the basis of their physical properties in order to guide nuclear medicine physicians in the choice of a radionuclide of first choice.