Analyse génomique des cancers médullaires de la thyroïde appliquée à l'étude comparative de l'oncogenèse humaine et murine

Les tumeurs neuro-endocrines sont rares et comprennent le cancer médullaire de la thyroïde (CMT) qui se développe aux dépens des cellules C. Le CMT est lié à une prédisposition génétique dans 30% des cas impliquant l oncogène RET. Les altérations géniques de l oncogenèse de ces tumeurs demeurent mal connues, et les thérapeutiques actuelles des formes agressives sont inefficaces. Dans ce contexte, mon travail de thèse a porté sur: l analyse de mutations dans des gènes liés aux voies de signalisation dans les tumeurs neuro-endocrines, dont le CMT; et l identification de signatures moléculaires par microarray des CMT humains et murins (souris RET634 et souris PRLR-/-). Ces travaux ont permis d identifier des profils géniques associés aux différents types de CMT en particulier permettant de distinguer les formes agressives de la maladie caractérisées par la surexpression de gènes impliqués dans la prolifération et l invasion tels PTN et ESM1. Ils ont permis également de caractériser les altérations géniques et chromosomiques survenant au cours de la progression des CMT, tel que la perte du chromosome 1p. Enfin, ils ont permis de valider les modèles murins de CMT comme outils intéressants pour l étude des CMT et l évaluation de nouveaux agents thérapeutiques in vivo.Neuro-endocrine tumors are rare, and comprise medullary thyroid carcinoma (MTC) which develops from C cells. RET oncogene mutations are found in familial MTC and in one third of sporadic cases. However, lack is known about molecular abnormalities involved in the progression of these tumors. Particularly, oncogenic mechanisms involved in non-RET mutated sporadic MTC remain unclear. Moreover current therapeutic of the aggressive forms still ineffective. In this context, this work aimed to characterize genes mutations status of neuro-endocrine tumors, as MTC; and to identify by microarray, molecular signatures of MTC in human and animal models (mice RET634 and PRLR -/-). We identified genes expression profiles associated with the various forms of MTC. These profiles permit to distinguish the aggressive forms characterized by overexpression of genes involved in proliferation and invasion such as PTN and ESM1. We also characterized molecular alterations occurring during MTC progression, especially loss of chromosome 1p. Finally, this study allowed validating the use of MTC mice model as useful tool for studying these tumors and testing new therapeutic agents in vivo.PARIS-BIUP (751062107) / SudocSudocFranceF

Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study

International audienceThis retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population