EXTH-55. PET, IMAGE-GUIDED HDAC INHIBITION OF PEDIATRIC DIFFUSE MIDLINE GLIOMA IMPROVES SURVIVAL IN MURINE MODELS

Abstract

Abstract 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 pharmacokinetics monitoring. These properties would be best determined clinically with image guided dosimetry using theranostic compounds, agents with both therapeutic and imaging properties. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging. We synthesized PETobinostat, a novel PET-imageable HDAC inhibitor, and showed its effectiveness against DIPG models in vitro and in vivo. Cell studies against a library of DIPG cells show nanomolar IC50, allowing for rapid in vivo translation. When injected in mice, PET shows the need of CED to achieve high brain concentrations, as systemic delivery yields inferior brain permeation. PET also shows that CED has significant mouse-to-mouse variability: imaging is used to modulate CED infusions to maximize tumor saturation over time. By determining condition-specific clearance half-life (ranging between 60 and 120 minutes), we maximized tumor permeation above therapeutic concentrations for at least 12 hours. This PET-guided approach resulted in decrease tumor cellularity (p= 0.001), increased apoptosis (p= 0.034), decreased dividing cells (p= 0.003), and recovery of histone-3 acetylation (p < 0.0001) when compared against vehicle and systemic-treated controls in tumor-bearing mice. Further, the PET-guided CED of PETobinostat resulted in survival prolongation (67.5 vs. 35 days, p = 0.0001) when compared to systemic administration of another potent HDAC inhibitor (Panobinostat). CED without PET guidance failed at improving survival (37.5 vs. 35 days, p = 0.74). No significant toxicity was observed following CED of PETobinostat. This work demonstrates how personalized image-guided drug delivery of a novel HDAC inhibitor may be useful in potentiating CED-based treatment platforms, and supports a foundation for the clinical translation of PETobinostat.