PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models
Menée in vitro et à l'aide de modèles murins de gliome médian diffus, cette étude met en évidence l'intérêt, pour améliorer la survie, d'une stratégie thérapeutique consistant à délivrer localement un nouvel inhibiteur d'histone désacétylase (PETobinostat) et à suivre la pénétration et la clairance du médicament à l'aide d'une tomographie numérique à émission de positrons afin d'optimiser la dose du médicament et la stratégie d'administration
Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetic monitoring. These properties would be best determined clinically with image-guided dosimetry using theranostic agents. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging and show how PETobinostat, a novel PET-imageable HDAC inhibitor, is effective against DIPG models. PET data reveal that CED has significant mouse-to-mouse variability; imaging is used to modulate CED infusions to maximize tumor saturation. The use of PET-guided CED results in survival prolongation in mouse models; imaging shows the need of CED to achieve high brain concentrations. This work demonstrates how personalized image-guided drug delivery may be useful in potentiating CED-based treatment algorithms and supports a foundation for clinical translation of PETobinostat.
Science Advances 2020