Microbubble-enhanced sonobiopsy could ‘revolutionize’ treatment of brain tumors
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Key takeaways:
- Sonobiopsy increased the amount of ctDNA from high-grade gliomas that bypassed the blood-brain barrier for examination.
- The technique could improve the way clinicians diagnose, monitor and treat patients.
Focused ultrasound could provide clinicians a safer alternative in diagnosing, monitoring and treating patients with brain tumors compared with biopsy, according to findings published in npj Precision Oncology.
Sonobiopsy, in combination with microbubbles, increased the amount of patient-specific circulating tumor DNA (ctDNA) in 60% of individuals with high-grade glioma in the prospective trial, one of which had their ctDNA almost double.
“This capability will be as impactful as an MRI scanner,” Eric C. Leuthardt, MD, professor and vice chair of innovation in the department of neurology at Washington University in St. Louis, told Healio. “I really believe that because now, through this approach, we can start to — in a safe and nondestructive way — molecularly interrogate the brain.”
How does sonobiopsy work?
Traditionally, a brain tumor diagnosis begins with an MRI or CT scan and is followed with a surgical resection. Biopsy comes with risks, however, including hemorrhage, infection and swelling of the brain.
Clinicians also use lumbar punctures and blood sampling, but lumbar punctures can be uncomfortable and cause adverse events, and using liquid biopsy on blood can be difficult because the blood–brain barrier prevents most ctDNA from escaping, according to background information provided by researchers.
“You can now really do a good job of anatomically interrogating the brain,” Leuthardt said. “You can use MRI to define how certain areas of the brain function, but getting particular information out of the brain essentially requires a surgical procedure, and that we saw as a fundamental barrier to treating and understanding a whole host of diseases.”
Leuthardt believes sonobiopsy can bypass that barrier.
Sonobiopsy uses low amounts of focused ultrasound on a specific portion of the brain.
Clinicians coregister the patient’s brain with a three-dimensional reconstruction built from MRI imaging.
Stereotactic navigation guides the ultrasound to designated spots, Leuthardt said.
Then, the patient receives an injection of FDA-approved microbubbles.
“When the microbubbles pass through that focused area of ultrasound, they expand and contract, and that’s what stretches the endothelium of the blood vessels to open up the blood–brain barrier in that very precise spot,” Leuthardt said. “That’s what allows us to give low energy that’s nondestructive, and that allows the opening of the blood–brain barrier so that biomarkers, such as circulating tumor DNA, can go into the bloodstream.”
Clinicians then compare blood specimens before and after the sonobiopsy.
“When you're doing a liquid biopsy, you’re looking for a needle in the haystack,” Leuthardt said. “Either you can try to have more sensitive assays to find that needle, or, as with sonobiopsy, you're increasing the number of needles in the haystack.”
A ‘significant increase’ in ctDNA
Leuthardt and colleagues tested sonobiopsy in a single-arm trial on five individuals (four men; average age, 60 years) with high-grade brain tumors who had already been scheduled for surgery to remove them.
Sonobiopsy produced a “significant increase” in ctDNA level in 80% of participants, and “significantly increased the detection of patient-specific tumor variant ctDNA” in 60%, researchers wrote.
The highest-recorded results included a 1.6-fold increase of mononucleosome ctDNA fragments, 1.9-fold for patient-specific tumor variant ctDNA, and 5.6-fold for the TERT mutation ctDNA level.
“The results are encouraging,” Leuthardt said. “This is a pilot trial. It’s early. We’re still refining our ultrasound parameters. We’re still refining our capabilities.”
The early results show signals of efficacy, including enhanced imaging and enriched biomarkers seen in patient blood samples, according to Leuthardt. Nevertheless, researchers did observe variability of results across the first five patients in the study.
“We still need to optimize how we use our ultrasound body and our ultrasound guidance to get the best signal possible,” Leuthardt said. “But as a first step, given that these are our first five subjects, I would consider this a home run.”
The next step includes optimizing the sonobiopsy. They conducted the focused ultrasound on a low setting out of an abundance of caution, Leuthardt explained. Determining when to administer the microbubbles and when to test the blood will be critical as well.
However, he does not expect any changes to impact the risk profile.
Researchers did not observe any adverse events. They also did not note any tissue damage on the brain, nor any fluctuations in heart rate or respiration.
“The risk for very transient, very localized opening of the blood–brain barrier is incredibly low,” Leuthardt said. “Because the blood–brain barrier opening is relatively limited, and the degree to which it mechanically opens and what it allows to release — really small molecules — there shouldn’t be any concern that you’re releasing tumor cells into the blood or anything that potentially creates safety problems.”
A ‘frame-shifting technology’
The potential applications for sonobiopsy could “revolutionize” the field and be a “frame-shifting technology” for studying the brain, Leuthardt said.
Beginning with brain cancer, he described three areas where it would be beneficial — diagnosis, monitoring and identification of recurrence.
Regarding diagnosis, if oncologists could determine the biology of a tumor through ctDNA, they could adjust how they proceed surgically.
“If, for instance, [a patient has an] IDH1 mutation, be aggressive to try to get a gross total resection because those patients do demonstrably better with gross total resection,” Leuthardt explained. “If it’s an IDH1 wild-type, then you don’t have to be as aggressive because the data [are] more fuzzy with gross total resection. There, you may be more focused on functional preservation. Understanding that upfront could really change your surgical strategy.”
Sonobiopsy could help identify how treatments and clinical trials are working on patients, he added.
“Let’s say, after you do your surgery, you complete radiation therapy,” Leuthardt said. “How is this tumor responding to the therapies that you’re throwing at it? Can you start to see a reduction in circulating tumor DNA because there’s a response to the tumor, or is it not changing? Maybe that agent is not working, or the epigenetic or the gene expressions are changing that can give you insights to how this tumor is evolving in response to the tumor. Those are all things that we can learn and act upon during the treatment phase of that tumor.”
Leuthardt then described how difficult it can be for multidisciplinary boards to determine whether a patient is experiencing a recurrence on imaging alone.
“Does that show expression evidence that’s consistent with a tumor or is it just changes induced by radiation?” he asked. “They should look very different from a gene expression and a molecular standpoint.”
Leuthardt also expressed optimism that sonobiopsy could be used in treatment of other brain diseases such as Alzheimer’s, psychiatric disorders and developmental disorders.
“What if we could get a sense of how DNA expression is changing?” he asked.
“Different biomarkers, such as proteins, metabolic indicators are changing either at baseline so that we could potentially characterize disease in a much more rigorous way,” he added. “It could certainly enhance clinical trials for pharmacological approaches — really understand this having a central effect as intended so that we now have the ability to say, here’s how, on the cellular level, a specific part of the brain is affected by the disease itself or affected by the treatment for that disease.”
For more information:
Eric C. Leuthardt, MD, can be reached at leuthardte@wustl.edu.
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