Ultrasound-created microbubbles can deliver anti-cancer drugs to tumors in difficult-to-reach areas such as the brain stem and spinal cord, a pilot study in children has revealed.
The microbubbles provide a potential entry point for treatments aimed at the central nervous system that are not usually able to traverse the blood-brain barrier.
Focused ultrasound (FUS) radiation temporarily opened this naturally protective barrier, which is designed to filter out molecules above a certain size to prevent toxins and infectious agents from reaching functional brain tissue.
The technique excited microscopic particles called microbubbles, causing them to expand and contract and temporarily increase the barrier’s permeability.
It enabled oral panobinostat to be delivered using a mobile device on an outpatient basis every other day to three children with relapsed diffuse midline gliomas (DMGs), without serious events.
“Lessons learned from this work can lead the effort toward translating combinatorial treatment approaches to improve outcomes for children with this fatal disease,” reported Cheng-Chia Wu, PhD, from Columbia University, and co-workers in Science Translational Medicine.
Diffuse intrinsic pontine glioma (DIPG) are a fatal class of brain tumor in children that have been more recently reclassified as diffuse DMG with histone H3 lysine-27–to–methionine (H3K27M) mutation.
The tumors arise in midline structures of the brain, most commonly the brainstem, followed by the thalamus and spinal cord.
Although a disease-defining genetic alteration in H3K27M has been identified, there remains no systemic treatment with the exception of radiotherapy that can temporarily control the cancer.
Surgery is of limited benefit, due to the impact of potential damage to a functionally important area such as the brainstem and the DMGs are largely diffuse, with microscopic extension into brain areas where the blood-brain barrier remains intact.
The prognosis for affected children is therefore dismal, with a median overall survival of just one year.
Most clinical trials examining blood brain barrier opening (BBBO) in adults have been designed with just one treatment of ultrasound over several weeks and little is known about the feasibility of using ultrasound at shorter intervals in children using a mobile device.
To investigate further, the researchers first conducted initial studies in a mouse model of DMG showing the additive benefits of FUS with panobinostat, a histone deacetylase inhibitor that has shown promise in treating DMG in vitro through multiple drug screening studies.
Although panobinostat has been found to be efficacious in vitro, the authors noted that it has limited therapeutic benefit in patients with DMGs and has limited penetrance into the brain parenchyma.
The team then set up a single-arm, first-in-pediatric trial to examine the feasibility of delivering neuronavigation-guided (Ng)FUS treatment combined with oral panobinostat.
The study, in children with relapsed DMGs, included an escalation of FUS delivery in the patients with progressive DMGs to assess the feasibility of opening multiple sites in the brain. FUS was delivered with the Ultra-Nav FUS device and concurrent oral panobinostat administration.
NgFUS successfully opened the blood when used as often as every two days, Wu and colleagues reported. Magnetic resonance imaging with contrast identified the region where the blood-brain barrier opened.
Overall, 22 FUS procedures were delivered for one tumor site and four FUS procedures were delivered for two tumor sites, all without sedation.
All three patients received treatment to one site without serious adverse events, and two of the patients received treatment to two sites, all without anesthesia or sedation. For treatment at two tumor sites, there was prolonged BBBO and one grade five event, that was unlikely to be related to FUS.
“In conclusion, NgFUS delivery–mediated BBBO is feasible as an outpatient procedure with patients with progressive DIPGs/DMGs,” the researchers reported.
