Could Focused Ultrasound Transform Brain Cancer Treatment?

Dr. Graeme Woodworth is opening the door to a promising new treatment for aggressive malignant brain cancer.

Focused ultrasound activating bubbles in the blood allow targeted chemotherapy to cross the blood-brain barrier.

Graeme F. Woodworth, MD, FACS, chief of neurosurgery at the University of Maryland Medical Center and the Howard M. Eisenberg, MD Distinguished Professor of Neurosurgery and chair of the Department of Neurosurgery at the University of Maryland School of Medicine, is advancing the treatment of glioblastoma, the most common and deadly primary brain cancer in adults. More than 14,000 Americans are diagnosed with glioblastoma each year. Patients typically survive only 12 to 18 months after a diagnosis because the cancer quickly spreads throughout the brain.

Although the initial tumor may be surgically removed, treatment to slow or stop the spread of cancerous cells is greatly hindered by one of the body’s natural defenses, the blood-brain barrier (BBB), which serves as a gatekeeper, protecting the brain by keeping mostly large and water-soluble chemicals — including most chemotherapy drugs — out.

Woodworth is exploring the use of MRI-guided focused ultrasound to enable chemotherapeutic and nanotherapeutic agents to cross the BBB and provide targeted treatment. His research is funded by grants from the National Cancer Institute and the National Institute of Neurological Disorders and Stroke, both within the National Institutes of Health.

Questions

What motivated you to explore using focused ultrasound to enable chemotherapy for brain cancer treatment?

The insight I had was, I could get better and better and better at surgery, specifically removing a primary brain tumor like glioblastoma and despite that, and despite temporarily improving that patient’s neurological function by removing that tumor (hopefully if we've done it well, if I've done it well, we haven’t hurt that patient neurologically, which is the goal, maximal tumor removal with maximum function preservation), if we can accomplish that key balance in the operating room more and more and more effectively, are we altering the natural history of the disease such that we're improving the outcomes for these patients and the insight I was having was more and more, no. Because the residual invasive disease that can't be resected without altering that patient’s neurological function is the ultimate cause of recurrence and patient succumbing to this disease, which unfortunately still happens within 18 months, which is the median survival for patients still to this day.

What is the blood-brain barrier and why has it been an obstacle to treating brain cancers with chemotherapy?

The blood vessels, as they change into becoming brain blood vessels, as the blood vessels are separated and covering and providing blood supply to the brain and the central nervous system, because the spinal cord is the same, the interface between the blood and the cells on the other side is actually multilayered and complex. That in science is referred to as the neurovascular unit because there are contributions from the neurons and the blood vessels, the components on the other side, and then the blood vessels themselves. So that neurovascular unit is referred to as the blood-brain barrier.

So, it's much more challenging to get things to move across that barrier in the brain as opposed to in the heart or in the kidney. Drugs that would cross into the heart from the bloodstream would not otherwise cross into the brain. It's estimated that 98 percent of current pharmaceutical drugs do not cross into the brain.

Getting therapies to move into the brain has been a huge challenge in medicine, and many efforts have been made to mitigate that barrier, either by developing technologies and systems that can cross the barrier from a biologic perspective, using shuttling systems, ways to disrupt the blood-brain barrier with osmotic changes and the salt concentration across the bloodstream, and then this technology that we've been developing where we actually activate circulating bubbles in the bloodstream temporarily within an acoustic field. With sound waves and in activating those bubbles locally within a region of the brain that temporarily perturbs and opens that blood-brain barrier through a biomechanical interaction, more so than a biological interaction.

How does it work?

If we can activate those circulating bubbles within the blood vessels within the acoustic field, then we see this effect. We see this temporary opening and un-gating of the blood-brain barrier and entities that are in the bloodstream that wouldn't otherwise go in, everything from small molecule drugs, dyes, fluorescent dyes, antibody therapeutics, larger molecules, nanoparticle therapeutics. They can now access and enter the brain, whereas before they were not able to do that, and that only happens where you locally sonicate and activate these bubbles and over a short period of time so it's not open for days. It's actually open for hours or less in some cases.  

How soon after surgery removes the bulk of the cancer do you employ this new therapy?

What we don't want to do is wait until the tumor already recurs, because once that's happened in the brain, we have patients likely having neurological problems and that tumor is now a heterogeneous, complex mass that's going to be harder to treat.

Traditional chemotherapy, as you would argue, just kind of bluntly, goes after the tumor by just causing essentially universal cell death to whatever takes up that drug. And so, we'd rather target the residual invasive tumor cells with focused ultrasound, get the drugs in, but have those drugs be tuned to treat the complex biology and not necessarily hurt the neurons and the other components of the brain. That's the real end goal here.