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Sunnybrook researchers first in the world to visually demonstrate that a cancer therapy can cross the blood-brain barrier using MRI-guided focused ultrasound.Kevin Van Paassen/Courtesy of Sunnybrook Health Sciences Centre

Canadian researchers are reporting positive results in their efforts to surmount one of the most daunting obstacles to the treatment of brain cancer: The blood-brain barrier.

After using focused ultrasound to temporarily loosen the tightly knit mesh of cells that line the blood vessels that serve the brain, scientists were able to demonstrate that a cancer drug that would otherwise be unable to penetrate the barrier had reached its target tumours in patients who were enrolled in the experiment.

“It’s incredibly promising for brain cancer, but also for any disease where the blood-brain barrier is a challenge to the delivery of therapeutics,” said Nir Lipsman, a neurosurgeon and scientist at Sunnybrook Health Sciences Centre in Toronto and principal investigator on the study.

The blood-brain barrier is a biological necessity that evolved to provide the body’s most crucial organ with an additional level of protection from infection and toxins that can enter through the bloodstream. However, it can also shield brain tumours from biological drugs tailored to attack them, including tumours whose locations may rule out surgery or other treatments.

The early phase clinical trial at Sunnybrook is the first to use focused ultrasound to aid the delivery of a drug across the barrier in humans. After the patients received up to six treatments, researchers showed the tumours were reduced in size by an average of about 20 per cent, a modest but substantial improvement for hard-to-reach tumours. However, Dr. Lipsman cautioned, the study was too small to draw firm conclusions about efficacy. Its primary purpose was to test the safety of focused ultrasound as an aid to chemotherapy for brain tumours and set the stage for a larger trial.

The study was published on Wednesday in the journal Science Translational Medicine.

Sunnybrook is among a handful of centres experimenting with focused ultrasound as a way to enhance therapies in the brain. Work more than a decade ago by Kullervo Hynynen, now Sunnybrook’s vice-president of research and innovation, helped lay the groundwork for recent studies.

In 2019, Dr. Lipsman and colleagues showed they could open the blood-brain barrier in specific areas for Alzheimer’s patients, but that study did not involve administering a therapy. It merely demonstrated such a strategy was possible should a drug become available. But from an early stage, Dr. Lipsman said, the team also set its sights on cancer in the brain.

“We know it’s a disease where a lot of advancements have been made in our understanding of the genetics and molecular profiling of these tumours. But not a lot of advancements have been made in our ability to prolong survival and improve quality of life,” he said.

The study involved four patients with metastatic Her2-positive breast cancer – a type that can grow and spread relatively rapidly. In some cases, cancer cells that enter the bloodstream can alter the blood-brain barrier and slip through to establish tumours. This had occurred in each of the subjects. Elsewhere in the body, Her2-positive tumours can be treated with the drug trastuzumab – also known by its brand name, Herceptin – which has a proven track record. However, the drug consists of proteins that are too large to easily cross the blood-brain barrier, so it generally has little impact on brain tumours.

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In 2019, Dr. Lipsman and colleagues showed they could open the blood-brain barrier in specific areas for Alzheimer’s patients, but that study did not involve administering a therapy.Kevin Van Paassen/Courtesy of Sunnybrook Health Sciences Centre

In the experiment, the patients were given the drug first without any other intervention to see if there was an effect. Next, they took the drug again, along with another infusion containing microscopic gas bubbles, which vibrate when stimulated by ultrasound and can spread apart the network of cells that make up the blood-brain barrier. For the treatment, participants were placed in an MRI machine so the researchers could image their tumours and focus the ultrasound in those areas. The drug was prepared with a radioisotope tracer developed by researchers at the University of Toronto. This allowed the Sunnybrook team to observe it in the MRI as it crossed the barrier. The patients experienced no ill effects beyond having to endure sessions of two to three hours in an MRI machine.

“From their perspective, it’s pretty anti-climactic,” Dr. Lipsman said. “We can do it as an outpatient procedure.”

Overall, the team reported uptake of the drug by tumours doubled with the ultrasound, and in some areas, the improvement was more than five times.

“These are exciting findings that confirm in patients what was previously known in preclinical studies, that [drug] uptake can be increased by several fold as a result of blood-brain barrier opening,” said Elisa Konofagou, a professor of biomedical engineering at Columbia University in New York who specializes in the medical use of ultrasound. Prof. Konofagou, who was not involved in the study, said the tracing and imaging that the team conducted was crucial for quantifying the benefits of the method.

Sadhana Jackson, a pediatric neuro-oncologist at the U.S. National Cancer Institute in Bethesda, Md., added that the technique shows potential for patients with limited treatment options, particularly when brain tumours are “progressing aggressively”.

“[I’m] excited to see future applications of this technology amongst the diversity of malignant brain tumors, varied-sized tumors and in both adults and children,” Dr. Jackson said.

Ying Meng, a resident physician at Sunnybrook and lead author on the study, said that is where the team hopes to go next.

“It is an exciting time,” Dr. Meng said, adding that the results show “focused ultrasound is a powerful noninvasive technology to help deliver advanced therapies to the brain.”

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