Focused Ultrasound and Microbubbles Show Promise in Delivering Chemotherapy to Childhood Brain Tumors
researchers have demonstrated the feasibility of using focused ultrasound (FUS) in combination with microbubbles to temporarily open the blood-brain barrier (BBB) and deliver the chemotherapy drug panobinostat to children with relapsed diffuse midline gliomas (DMGs), a especially aggressive type of brain tumor. The study, published in Science Translational Medicine, represents a potential step forward in treating this currently incurable disease.
DMGs, often arising in the brainstem, thalamus, or spinal cord, are characterized by a specific genetic mutation (H3K27M) and have a dismal prognosis, with a median overall survival of just one year. Current treatment options are limited to radiotherapy, and surgery is frequently enough impractical due to the tumors’ location and diffuse nature. A major challenge in treating these tumors is the BBB, which effectively shields the brain from many therapies.
The research team, led by Cheng-Chia Wu, PhD, from Columbia University, utilized FUS to excite microscopic bubbles injected into the bloodstream. This caused the bubbles to expand and contract,gently and temporarily increasing the permeability of the BBB,allowing panobinostat – a histone deacetylase inhibitor showing promise in vitro – to reach the tumor.
Prior studies in mouse models had indicated a synergistic effect between FUS and panobinostat. Building on this, the researchers conducted a first-in-pediatric clinical trial involving three children with relapsed DMGs.The FUS treatment was delivered using a mobile ultra-Nav FUS device, allowing for outpatient administration of oral panobinostat every other day.
The study successfully opened the BBB, as confirmed by magnetic resonance imaging, with treatments delivered as frequently as every two days. A total of 22 FUS procedures were performed targeting single tumor sites, and four procedures targeted two sites. Importantly, the procedures were conducted without sedation or anesthesia for the initial single-site treatments.
While treatment at a single tumor site was well-tolerated, extending treatment to two sites resulted in prolonged BBB opening and one serious adverse event (grade five), though researchers believe this event was unlikely to be directly related to the FUS procedure.
The researchers conclude that neuronavigation-guided FUS (NgFUS) mediated BBB opening is a feasible outpatient procedure for children with progressive DIPGs/DMGs, paving the way for further inquiry of combinatorial treatment approaches to improve outcomes for these patients. The findings also address a gap in knowledge regarding the feasibility of frequent ultrasound application in children using portable devices.