PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models

• Published in: Science advances Vol. 6; no. 30; p. eabb4105
• Main Authors: Tosi, Umberto, Kommidi, Harikrishna, Adeuyan, Oluwaseyi, Guo, Hua, Maachani, Uday Bhanu, Chen, Nandi, Su, Taojunfeng, Zhang, Guoan, Pisapia, David J, Dahmane, Nadia, Ting, Richard, Souweidane, Mark M
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.07.2020
• Subjects: Animals; Brain Stem Neoplasms - pathology; Cancer; Convection; Disease Models, Animal; Drug Delivery Systems - methods; Glioma - diagnostic imaging; Glioma - drug therapy; Glioma - pathology; Humans; Mice; Positron-Emission Tomography; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abb4105

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.