Sound waves help treat brain tumors


A first human study reported in Science Translational Medicine today (October 13th) demonstrates the delivery of an immunotherapeutic drug to metastatic brain tumors with the help of focused ultrasound. The targeted low-frequency sound waves temporarily opened the normally impenetrable blood-brain barrier at the tumor sites in breast cancer patients in stage 4, thus enabling access to medication. Follow-up analyzes showed that the procedure also resulted in tumor shrinkage.

“It’s a really important step in the process to understand how valuable focused ultrasound will be as a method of delivering drugs to the brain,” says Richard Daneman, neuroscientist of the University of California at San Diego, who studies the blood Brain barrier studied but was not part of the research team.

“The fact that they showed increased drug delivery where they tried to attack – that’s pretty cool,” adds Choi-Fong Cho, a neurosurgery researcher from Brigham and Women’s Hospital and Harvard Medical School, who is also not at the Study participated.

The brain is a problematic organ to treat, explains Cho, because it has a built-in defense shield in the form of the blood-brain barrier – a specialized endothelial lining of the brain’s blood vessels that prevents large molecules from leaking into the surrounding nerve cells . The barrier is highly effective at preventing pathogens and toxins from getting into the brain, Cho says, but it also blocks drugs. “When it comes to treating diseases in the brain,” she says, “it’s really a big challenge.”

One way to get around this problem is to inject therapeutics directly into the brain, but such injections are technically complex and can require surgical creation of an opening in the skull. So the researchers looked for a way to temporarily cross the blood-brain barrier without the need for surgery – and over a decade ago they discovered they could use sound.

Gas-filled lipid microbubbles, originally developed as contrast agents for ultrasound imaging, are injected into the bloodstream and when ultrasound beams are directed at a specific location, the bubbles in that region wobble and destroy the vessel walls. In animal experiments, the technique known as focused ultrasound has been used to treat brain diseases. But in humans it has only been tested for feasibility and safety – to confirm that permeabilization is occurring and is rapidly dissolving.

See “Ultrasound opens the blood-brain barrier in Alzheimer’s patients”

In this latest human study, neurosurgery researcher Nir Lipsman of the Sunnybrook Research Institute and his colleagues took the technology a step further, showing that focused ultrasound enables a drug to penetrate brain tumors and possibly even shrink them.

Lipsman’s team performed the technique on four patients between the ages of 31 and 56, all of whom were regularly receiving the immunotherapy drug tratuzumab for the treatment of metastatic Her2-positive breast cancer. Her2-positive cancers are those in which the cells produce large amounts of the human epidermal growth factor receptor 2, which drives the growth of the cancer. Tratuzumab is a monoclonal antibody that blocks Her2. It can be effective at shrinking tumors in the body, but it doesn’t penetrate the brain, explains Lipsman.

See “New Understanding of Metastases Could Lead to Better Treatments”

The women received a small amount of radiolabelled tratuzumab along with their normal dose to allow imaging of the drug both before and after their brain tumors were treated with the focused sound waves. Imaging the women’s brains with single photon emission computed tomography (SPECT) showed that the focused ultrasound roughly doubled the amount of radioactivity detectable in the brain lesions from baseline, Lipsman says, showing that the drug had penetrated successfully.

The helmet used to deliver focused ultrasound beams to patients’ brain tumors

DOUG NICHOLSON, SUNNYBROOK HEALTH SCIENCES CENTER

The procedure, performed several times on each patient, did not cause serious side effects – all patients were discharged from the hospital on the same day. In addition, the following day, magnetic resonance imaging (MRI) confirmed that the blood-brain barrier was closed.

Follow-up MRIs done in the following months showed that all women had a shrinkage in brain tumor size that varied between 31 and 7 percent. There was no control group.

“It is so difficult to make blanket conclusions about efficacy in just four patients, but of course that is a promising signal,” says Lipsman, hoping that large-scale controlled trials can begin soon.

Even without concrete evidence that the technique shrinks tumors, the paper is a big step forward for focused ultrasound, says University of Maryland neurosurgeon Graeme Woodworth, who was not involved in the project. It shows the technique can work with a great immunotherapy drug, he says, and for the first time tracks the drug’s location in patients. “Overall, it’s very exciting.”



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