Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma

Masih Tazhibi, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Nicholas McQuillan, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Hong-Jian Wei, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Matthew Gallitto, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Ethan Bendau, Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
Andrea Webster Carrion, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Xander Berg, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Danae Kokossis, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.
Xu Zhang, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Zhiguo Zhang, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Chia-Ing Jan, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
Akiva Mintz, Department of Radiology, Columbia University, New York, NY, 10027, USA.
Robyn D. Gartrell, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Hasan R. Syed, Department of Neurosurgery, Children's National Hospital, Washington, DC, USA.
Adriana Fonseca, George Washington University, Washington, DC, USA.
Jovana Pavisic, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Luca Szalontay, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA.
Elisa E. Konofagou, Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
Stergios Zacharoulis, Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Columbia University Irving Medical Center, 161 Fort Washington Avenue, New York, NY, 10032, USA. sz2764@cumc.columbia.edu.
Cheng-Chia Wu, Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA. cw2666@cumc.columbia.edu.

Document Type

Journal Article

Publication Date

3-30-2024

Journal

Journal of translational medicine

Volume

22

Issue

1

DOI

10.1186/s12967-024-05096-9

Keywords

Blood–brain barrier opening; Diffuse midline glioma; Focused ultrasound; Radiotherapy

Abstract

BACKGROUND: Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood-brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. METHODS: To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB, H3.3K27M, p53). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). RESULTS: FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT. CONCLUSION: Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

Department

Neurological Surgery

Link to Full Text

Share

COinS