Development and validation of a cellular model to study the 18FES efficiency in PET imaging: application to ER mutated breast cancer
Développement et validation d’un modèle cellulaire pour l’étude de la performance du 18FES en imagerie TEP: Application aux cancers mammaires ER mutés
Résumé
Breast cancer (BC) is the deadliest cancer in women in France and the most common in the world (World Health Organization, 2020). BC is classified into 5 distinct subtypes based on the expression of 3 different receptors: the EGF type 2 receptor (HER2), the progesterone receptor (PR) and the estrogen receptor (ER). More than 70% of BC cases express ER+ receptor which is associated to a 10% increase in the 5-year survival rates. However, during relapses, this survival rate decreases, and ESR1 mutations appear in tumor cells in a proportion of 10 to 50% of cases. Currently, 62 mutations have been identified, mainly located in the ligand-binding domain. Nowadays, molecular imaging using Positron Emission Tomography (PET) is widely used with fluorodeoxyglucose (FDG), the most common radiotracer for tumor cell detection. However, this radiotracer is unable to inform on ER mutation status. For that purpose, 18fluoroestradiol (18FES) already used to study ER expression in BC by PET imaging could also address this concern but its ability to bind to different mutants needs to be studied. The aim of this work is to investigate the affinity of 18FES for the most common ESR1 mutations as it could give the opportunity to determine the tumor status at diagnosis and adapt the therapeutic strategy accordingly. To achieve this, we have developed an inducible breast cancer cell model based on the use of a Tet-ON system. Six clones corresponding to the most frequent mutations found in patients at the metastatic stage (Y537S/C/N, D538G, E380Q and L536H) were generated. In vitro assays were performed to validate the inducibility and functionality of the system. Finally, the system has been tested and validated in vivo with an orthotopic mice model and by ex vivo IHC experiments. MicroPET experiments will soon be carried out in order to estimate the SUV (standardized uptake value) of 18FES for each mutation. All these findings should allow to precise the use of 18FES in PET imaging for the diagnosis and the patient therapy monitoring with ER+ breast cancers.
Domaines
Imagerie médicale
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