Feature

Focused ultrasound to open blood-brain barrier could transform glioblastoma treatment delivery

Graeme F. Woodworth

A pivotal trial is underway at University of Maryland Medical Center to evaluate the safety of MRI-guided focused ultrasound for opening the blood-brain barrier in patients undergoing surgery for glioblastoma.

“The ability to temporarily disrupt the blood-brain barrier while causing minimal brain tissue damage has the potential to dramatically alter the landscape of drug delivery to the brain for many diseases,” Graeme F. Woodworth, MD, FACS, professor of neurosurgery at University of Maryland School of Medicine and director of the Brain Tumor Treatment and Research Center at University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, said in a press release. “If successful, this approach would allow us to use chemotherapy and other therapies in the brain in ways that are currently not possible.”

Another trial will assess focused ultrasound for patients with newly diagnosed glioblastoma who receive standard temozolomide chemotherapy.

“If we can selectively open the blood-brain barrier, then in the future we could give a much lower dose of powerful drugs, which would likely reduce toxic side effects and make treatments safer as well as more effective for patients,” Woodworth said in the release.

HemOnc Today spoke with Woodworth about how the trial came about, the need for effective methods to allow cancer-fighting drugs to cross the blood-brain barrier, and the potential implications if this approach is proven safe and effective.

 

Question: How did this trial come about?

Answer: There has been a lot of work conducted by numerous groups around the world related to using this technology in the brain. It has been tested in different types of animals, all the way up to nonhuman primates. A group at University of Toronto, led by some of the leaders in the field, started the first clinical trial in North America in which focused ultrasound was used to open the blood-brain barrier in patients with brain cancer and other brain diseases. When we began this trial, we looked at how we could make a similar step toward testing this technology for patients in the United States, because the regulatory environment is different than it is in Canada and other places around the world. In this trial, we are treating patients with focused ultrasound before surgery. With this approach, we will be able to look at ultrasound-treated tissue to see if we have achieved the desired effect without causing significant damage. This will enable us to move toward the ultimate goal of using the ultrasound technology to improve drug delivery in the brain.

 

Q: What is the rationale behind this approach and how does it work?

A: The first step is to test whether this approach is safe for patients with brain cancer. We will do this by examining the tissue after surgery as we would examine any other biopsy or lesion in the brain with pathologic techniques. The focused ultrasound is applied in the MRI scanner using many beams of ultrasound energy that together are able to create the effect in a highly-targeted, controlled fashion within the brain. The ultrasound mode used for the blood-brain disruption approach leverages intravascular ultrasound agents, dubbed microbubbles, that are approved for use among patients for tests such as echocardiograms. The microbubbles are in the circulation for a short time — about 2 minutes on average — during which they can be stably oscillated within the blood vessels by the ultrasound energy. The oscillation of the microbubbles leads to the permeabilization effect on the blood-brain barrier.

 

Q: Can you explain the need for strategies that allow cancer-fighting drugs to cross the blood-brain barrier?

A: One of the ways we look at the blood-brain barrier in brain tumors or in any brain disease is by contrast enhancement on MRI and CT scans. This is circulating dye that generally remains in the bloodstream unless the vasculature is damaged or not completely formed. When either of these conditions exist, the contrast dye leaks into the surrounding tissues, and this is referred to as contrast enhancement. We use this approach to look at the blood vessels in the brains of all patients with brain cancer, and we also study what happens after focused ultrasound to see if we have opened the blood-brain barrier. In most glioblastoma cases, there are areas of contrast enhancement in the tumor and noncontrasting areas in the tumor. We are most interested — especially from a surgical perspective — in delivering treatment to those nonenhancing areas of the brain tumor, which we believe are filled with brain-invading tumor cells that generally are not resectable. Those areas of the brain still have functioning neural circuits and blood vessels. If we can treat those areas of the residual brain tumor, then we may have much more effective treatment strategies for these almost universally fatal tumors.

Q: What is the timeline for trial completion and data availability?

A: We expect to complete the trial and make data available within 1 year.

 

Q: What is the potential impact if this approach is proven safe and effective?

A: We already are moving forward with the second study, which will be performed within the context of the current standard of care for patients with brain cancer. That study will assess whether we can safely apply focused ultrasound while patients are receiving temozolomide chemotherapy. We also are going to look at whether we are improving the delivery of temozolomide into those brain regions that receive the ultrasound, but this is a secondary component to the study. If these two studies show we can safely apply ultrasound before surgery and in the setting of the current chemotherapy strategy, then we can move forward with an efficacy study in which we can use the ultrasound technology to improve the therapeutic effect of a specific drug or drug combination.

 

Q: Is there anything else that you would like to mention?

A: It is important to note that major research efforts have been carried out to get to the point where the FDA is comfortable allowing us to move forward. What we are doing now seems quite simplistic in a way, but it is an important step and all the research that has come before this has set the framework. We are hopeful that we can move this technology forward, because we know the blood-brain barrier is a critical limitation to our current therapeutic strategies. – by Jennifer Southall

 

For more information:

Graeme F. Woodworth, MD, can be reached at University of Maryland, Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201; email: gwoodworth@som.umaryland.edu.

 

Disclosure: Woodworth reports no relevant financial disclosures.

Graeme F. Woodworth

A pivotal trial is underway at University of Maryland Medical Center to evaluate the safety of MRI-guided focused ultrasound for opening the blood-brain barrier in patients undergoing surgery for glioblastoma.

“The ability to temporarily disrupt the blood-brain barrier while causing minimal brain tissue damage has the potential to dramatically alter the landscape of drug delivery to the brain for many diseases,” Graeme F. Woodworth, MD, FACS, professor of neurosurgery at University of Maryland School of Medicine and director of the Brain Tumor Treatment and Research Center at University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, said in a press release. “If successful, this approach would allow us to use chemotherapy and other therapies in the brain in ways that are currently not possible.”

Another trial will assess focused ultrasound for patients with newly diagnosed glioblastoma who receive standard temozolomide chemotherapy.

“If we can selectively open the blood-brain barrier, then in the future we could give a much lower dose of powerful drugs, which would likely reduce toxic side effects and make treatments safer as well as more effective for patients,” Woodworth said in the release.

HemOnc Today spoke with Woodworth about how the trial came about, the need for effective methods to allow cancer-fighting drugs to cross the blood-brain barrier, and the potential implications if this approach is proven safe and effective.

 

Question: How did this trial come about?

Answer: There has been a lot of work conducted by numerous groups around the world related to using this technology in the brain. It has been tested in different types of animals, all the way up to nonhuman primates. A group at University of Toronto, led by some of the leaders in the field, started the first clinical trial in North America in which focused ultrasound was used to open the blood-brain barrier in patients with brain cancer and other brain diseases. When we began this trial, we looked at how we could make a similar step toward testing this technology for patients in the United States, because the regulatory environment is different than it is in Canada and other places around the world. In this trial, we are treating patients with focused ultrasound before surgery. With this approach, we will be able to look at ultrasound-treated tissue to see if we have achieved the desired effect without causing significant damage. This will enable us to move toward the ultimate goal of using the ultrasound technology to improve drug delivery in the brain.

 

Q: What is the rationale behind this approach and how does it work?

A: The first step is to test whether this approach is safe for patients with brain cancer. We will do this by examining the tissue after surgery as we would examine any other biopsy or lesion in the brain with pathologic techniques. The focused ultrasound is applied in the MRI scanner using many beams of ultrasound energy that together are able to create the effect in a highly-targeted, controlled fashion within the brain. The ultrasound mode used for the blood-brain disruption approach leverages intravascular ultrasound agents, dubbed microbubbles, that are approved for use among patients for tests such as echocardiograms. The microbubbles are in the circulation for a short time — about 2 minutes on average — during which they can be stably oscillated within the blood vessels by the ultrasound energy. The oscillation of the microbubbles leads to the permeabilization effect on the blood-brain barrier.

 

Q: Can you explain the need for strategies that allow cancer-fighting drugs to cross the blood-brain barrier?

A: One of the ways we look at the blood-brain barrier in brain tumors or in any brain disease is by contrast enhancement on MRI and CT scans. This is circulating dye that generally remains in the bloodstream unless the vasculature is damaged or not completely formed. When either of these conditions exist, the contrast dye leaks into the surrounding tissues, and this is referred to as contrast enhancement. We use this approach to look at the blood vessels in the brains of all patients with brain cancer, and we also study what happens after focused ultrasound to see if we have opened the blood-brain barrier. In most glioblastoma cases, there are areas of contrast enhancement in the tumor and noncontrasting areas in the tumor. We are most interested — especially from a surgical perspective — in delivering treatment to those nonenhancing areas of the brain tumor, which we believe are filled with brain-invading tumor cells that generally are not resectable. Those areas of the brain still have functioning neural circuits and blood vessels. If we can treat those areas of the residual brain tumor, then we may have much more effective treatment strategies for these almost universally fatal tumors.

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Q: What is the timeline for trial completion and data availability?

A: We expect to complete the trial and make data available within 1 year.

 

Q: What is the potential impact if this approach is proven safe and effective?

A: We already are moving forward with the second study, which will be performed within the context of the current standard of care for patients with brain cancer. That study will assess whether we can safely apply focused ultrasound while patients are receiving temozolomide chemotherapy. We also are going to look at whether we are improving the delivery of temozolomide into those brain regions that receive the ultrasound, but this is a secondary component to the study. If these two studies show we can safely apply ultrasound before surgery and in the setting of the current chemotherapy strategy, then we can move forward with an efficacy study in which we can use the ultrasound technology to improve the therapeutic effect of a specific drug or drug combination.

 

Q: Is there anything else that you would like to mention?

A: It is important to note that major research efforts have been carried out to get to the point where the FDA is comfortable allowing us to move forward. What we are doing now seems quite simplistic in a way, but it is an important step and all the research that has come before this has set the framework. We are hopeful that we can move this technology forward, because we know the blood-brain barrier is a critical limitation to our current therapeutic strategies. – by Jennifer Southall

 

For more information:

Graeme F. Woodworth, MD, can be reached at University of Maryland, Department of Neurosurgery, 22 S. Greene St., Suite S12D, Baltimore, MD 21201; email: gwoodworth@som.umaryland.edu.

 

Disclosure: Woodworth reports no relevant financial disclosures.