Thèse de doctorat en Pharmacologie expérimentale et clinique
Sous la direction de Francis Lévi.
Soutenue le 04-11-2011
à Paris 11 , dans le cadre de Ecole doctorale Innovation Thérapeutique : du Fondamental à l'Appliqué (2000-2015 ; Châtenay-Malabry, Haut-de-Seine) , en partenariat avec Rythmes biologiques et cancers (Villejuif, Val-de-Marne) (laboratoire) .
L'objectif principal de ma thèse est l’exploration de l’impact clinique d’une perturbation du système circadien chez les patients cancéreux. J’ai démontré une relation robuste entre le rythme d'activité-repos et survie, symptômes et qualité de vie. J’ai mis en évidence et caractérisé la dynamique du système circadien des patients sous chimiothérapie. J’ai montré qu’une bonne tolérance conditionnait l’efficacité de la chronothérapie. Ces résultats me conduisent à proposer de cibler le système circadien pour améliorer les symptômes des patients et l’efficacité des traitements anticancéreux.
The circadian timing system : therapeutic target for preventing or improving the symptoms associated with cancer and its treatments
The circadian timing system controls several temporal aspects of physiology and behaviour in laboratory animals and humans. The disruption of the circadian timing system results in the occurrence of alterations at various levels of organisation: central coordination, circadian physiology, molecular clocks and signalling pathways. In particular, a circadian disruption induced by long-haul flights across several time-zones or by shift work is associated with the appearance of systemic symptoms, such as fatigue, mood disorders and appetite loss. These symptoms, related to circadian disruption, are also frequently found in cancer patients, as a consequence of their neoplastic disease or its treatment. My PhD work is part of the research regarding the role of the circadian timing system in the development of the symptoms associated with cancer and its treatment, in tumor progression and in patients’ survival. Its perspective is to identify novel therapeutic options. In particular, the general objectives of this thesis consist in the definition of the relationships between symptoms and circadian function of patients before and during chemotherapy, and in the quantification of the clinical impact of circadian disruption on quality of life and survival. I have focused in particular on patients with metastatic colorectal cancer, third cancer for incidence and mortality. These studies confirm the role of the circadian timing system in the occurrence of systemic symptoms in cancer patients, without treatment or during it. This study is currently ongoing in collaboration with the NIH in the United States. In conclusion, this work leads me to propose an innovative therapeutic approach aimed at shielding and/or restoring the integrity of the circadian timing system. This novel strategy should improve the therapeutic index of chemotherapy, by increasing its efficacy and decreasing its toxicity, still reducing the occurrence of symptoms, preserving the quality of life and prolonging the survival of cancer patients. The implementation of this strategy relies on the non-invasive monitoring of biomarkers of the circadian timing system and on the personalization of chronotherapy delivery.