The State of Care: The Brain

By Christine Yu | Portraits by Jörg Meyer

During his residency in radiation oncology at Columbia, radiation oncology faculty member Cheng-Chia Wu, MD, PhD, spent nine months working in the lab of Elisa Konofagou, PhD, a faculty member in radiology at VP&S and engineering at Morningside. While pursuing research is not uncommon among medical students and residents, the cross-disciplinary collaboration between radiation oncology and bioengineering was unusual. 

Dr. Konofagou has pioneered the use of focused ultrasound, a noninvasive technology, to open the blood-brain barrier temporarily and has worked with colleagues across campus to use the technology in treating Alzheimer’s, Parkinson’s, and brain cancer. “It sounded like an amazing tool to fight cancer,” says Dr. Wu. He asked Dr. Konofagou if she would teach him and explore whether the technology could be used to treat brain cancer. “It was the perfect match—the right timing, the interest—to work together,” he says.

When it comes to diseases of the brain, treatment is often a combination of science, art, and a little magic. Bringing those pieces together requires collaboration—within the clinical environment, in the laboratory, and across departments. “It’s about translational research, taking something all the way from the clinic or the OR to the laboratory and back. The diversity and breadth of that kind of effort requires multiple expertise,” says Peter Canoll, MD, PhD, director of neuropathology. “It wouldn’t be possible if we weren’t working in such a collaborative environment.”

VP&S faculty members are pioneering new ways to treat aggressive and drug-resistant conditions of the brain. These innovations have the potential to transform patient care through improved outcomes. 

Bypassing the Blood-Brain Barrier

For brain tumors, including glioblastomas, standard treatment usually involves surgery to resect as much of the tumor as possible, followed by chemotherapy and radiation. Even then, “these tumors still grow back 100% of the time,” says Jeffrey Bruce, MD, co-director of the Brain Tumor Center. The median survival rate is just over 12 months. 

The biggest obstacle isn’t necessarily the cancer; it’s the blood-brain barrier that keeps toxins and infectious agents away from the brain but also blocks therapeutic medications.

“The problem isn’t that we don’t have good drugs. The problem is that the drugs can’t get into the brain safely at levels that are effective at killing tumor cells,” Dr. Bruce says. Doctors can try to bypass the barrier by administering stronger doses but that typically leads to debilitating side effects and leaves brain tumors under-treated.

For the past decade, Dr. Bruce has worked to develop a way to transport drugs directly into the brain called convection-enhanced delivery. Surgeons implant a catheter in the vicinity of the tumor using stereotactic techniques. The catheter is attached to a pump that provides a continuous infusion of therapeutics.

“If you infuse the medication very slowly, it sets up a pressure gradient at the catheter tip, which pushes the drugs into the microscopic space around the tumor,” Dr. Bruce says. “The concentration of drugs you can get with this are 1,000-fold greater than anything you could possibly hope to achieve with intravenous or oral drugs.” This method also avoids systemic toxicity and side effects that most chemotherapies cause.

Earlier versions of the prototype required an external pump. But doctors could provide a single treatment only over four days before they had to remove the catheter because of the risk of infection. “To be effective, chemotherapy needs to be given multiple times and for longer periods of time,” Dr. Bruce says. “That became the new problem.”

The current prototype is completely internal, eliminating the risk of infection. The pump (the size of a hockey puck) is implanted in the abdomen. Tubing is tunneled under the skin and connected to the catheter in the head. The pump is controlled by wireless technology and can be refilled via a port and a syringe.

Physicians can now deliver a higher concentration of drugs for longer. In a trial of five patients with recurrent glioblastoma, patients received four rounds of treatment over one month—two days of infusion with the chemotherapy drug topotecan followed by a five-to-seven-day washout period before the next infusion. Dr. Bruce’s lab has shown that topotecan, a chemotherapy drug typically used to treat lung cancer, is effective in killing active tumor cells and doesn’t damage brain tissue in animal models.

The results of the phase 1 trial, published in a 2022 issue of Lancet Oncology, showed that this technique effectively killed the proliferating tumor cells and was not toxic to the surrounding noncancerous brain cells.

The researchers also did something unprecedented: They took multiple MRI-localized biopsies before and after treatment and analyzed the tissue to study the individual cell’s molecular biology, histology, and genomics. “This is totally unique. I don’t know of any other trial that’s ever done that in a brain tumor setting,” says Dr. Canoll.

This allowed the team to study the population of nonproliferating, quiescent cells left behind, the population of cells doctors worry about because they can lead to recurrent tumors. Peter Sims, PhD, a systems biology researcher who focuses on development of new technology to apply systems biology in patient care, used advanced single cell sequencing to characterize the cellular and molecular signatures of the cells. The researchers used the sequencing to identify potential drugs that could target these residual cells and work with topotecan. They hope to take this combination to a clinical trial.

The idea of leveraging local delivery could signify a paradigm shift not only for brain tumor treatment but for other brain diseases. “Most neurological diseases—Parkinson disease, epilepsy, Huntington’s disease, and Alzheimer’s—don’t have very effective treatments. We have some drug treatments, but they work modestly, and, in many cases, there are a lot of side effects,” Dr. Bruce says. This drug delivery system, and its ability to bypass the blood-brain barrier, could offer a solution. “It opens up a whole new area of how we treat brain diseases.” (Read more about the Irving Cancer Drug Discovery Program that supports the work of Drs. Bruce and Canoll.)

A New Paradigm

On another part of campus, Dr. Wu and his colleagues are also looking for ways to circumvent the blood-brain barrier. Preliminary data from Dr. Wu’s research during his residency garnered a lot of excitement for the potential of focused ultrasound as a tool to deliver therapeutics in the treatment of aggressive pediatric brain cancer. 

While ultrasound is commonly used to image the body—the heart, breast, and abdominal organs—and to monitor fetal development, Dr. Konofagou’s pioneering use of focused ultrasound for therapeutic intervention has put Columbia at the forefront of studying the use of this technique in a variety of other settings, including neurodegenerative disease and tumors.

What differentiates focused ultrasound is its noninvasive nature. Microbubbles—gas-filled, lipid-coated bubble solution—are injected intravenously and travel to the target site in the brain. Once there, beams of ultrasound are directed to the area of the tumor. “The sound waves have a frequency, and the microbubbles start growing and shrinking to the rhythm of the beat,” Dr. Wu says, like they are dancing. 

This interaction causes a disruption, mechanically separating the cells of the blood-brain barrier. The barrier becomes temporarily permeable, which allows drugs to reach the brain. In animal studies, Dr. Konofagou, Dr. Wu, and colleagues have shown that this technique is safe and effective. The technique also allowed physicians to treat tumors with a higher dose of chemotherapy medication without harming the surrounding brain tissue. 

Using the focused ultrasound system that Dr. Konofagou’s team built to open the blood-brain barrier safely in patients, Dr. Wu, pediatrician Luca Szalontay, MD, and others, through the Initiative for Drug Delivery Innovations for Childhood Brain Tumors, are leading a clinical trial to test the feasibility of the system to treat pediatric patients with diffuse midline glioma. Median survival for midline glioma, which is diagnosed in between 200 and 300 children in the United States each year, is nine to 12 months from diagnosis.

The team plans to treat 10 patients by using ultrasound then confirm through MRI that the blood-brain barrier opened. Patients will take oral etoposide daily for 21 days. Jovana Pavisic, MD, a pediatric oncologist, used mathematical modeling to predict which drugs would be most effective, based on RNA sequencing data and analysis.

“We chose etoposide because this medicine has an oral version,” Dr. Wu says. “We’re really hoping to keep the kids out of the hospital as much as possible. If they don’t have to get infusions, it makes life easier.” After 21 days of treatment, patients will have one week of rest before continuing for four cycles of chemotherapy. 

If this proof-of-concept trial demonstrates the ability to deliver a drug across the blood-brain barrier safely and effectively, it would create numerous opportunities to improve patient care. Dr. Wu says it opens the doors for medications that previously failed to show any benefit in treating brain tumors. What if those drugs were delivered through this mechanism? Would they work better? “There’s a big component of hope,” he says.

What’s more, the research team will collect blood that escapes from behind the blood-brain barrier, which may carry genetic material from the cancer. It could offer doctors insight into the cancer and how to adjust treatments. “It creates opportunities for surveillance and prevention,” Dr. Wu says. “Instead of doing biopsies, could we use sound waves to open the blood-brain barrier and make a diagnosis through that? Can we predict how the brain tumor will respond to treatments and can we more efficiently fight the tumor with targeted therapy?”

The Initiative for Drug Delivery Innovations was established with support from the Fegel Family Foundation and sustained support of Hope and Heroes. In addition to supporting new technologies with focused ultrasound, the initiative also supported a phase 1 trial using convection-enhanced delivery of MTX110, a water soluble form of panobinostat, to the brainstem of children with a type of fatal brain tumor known as diffuse intrinsic pontine glioma. These advancements in the treatment of childhood brain tumors are only made possible through the multidisciplinary collaborations of neurosurgery, pediatrics, bioengineering, pathology & cell biology, radiology, and radiation oncology at Columbia.

Dr. Konofagou’s group is also working with colleagues in neurology to carry out clinical studies to determine the effect of focused ultrasound in mitigating neurodegenerative diseases such as Alzheimer’s and Parkinson.

Expanding Minimally Invasive Options

Patients with drug-resistant epilepsy sometimes feel there aren’t any good options. Fewer than 3% will become seizure-free with additional medication.

While open surgical resection can potentially prevent seizures and improve neurological function in appropriately selected patients, the procedure is underutilized. “Very few patients are actually referred or evaluated for these procedures,” says neurosurgeon Brett Youngerman, MD. It’s an invasive procedure and some are worried that surgery will lead to worse neurological function. “We often see patients who have been on five or 10 medications for 10 to 20 years before they’re willing to consider surgery as a last resort.” 

Dr. Youngerman, along with Guy McKhann, MD, and other VP&S faculty, is working to develop minimally invasive, patient-centered treatment options for patients who have epilepsy that doesn’t respond to standard medication. One emerging treatment is magnetic resonance-guided laser interstitial thermal therapy, or MRgLITT. Doctors can selectively target and remove areas of the brain where they believe the seizures originate.

It’s part of an evolution within epilepsy surgery toward less invasive procedures. Laser ablation was initially developed to treat other diseases. “It quickly became clear that it would be useful in the brain where we often are trying to reach deep structure and we don’t want to cause damage to the overlying area,” Dr. Youngerman says. 

Because laser ablation is minimally invasive, patients think about it differently. “It’s opening up the door to many patients with drug-resistant epilepsy who otherwise were unwilling to consider surgical options because they perceived them to be too invasive,” says Dr. Youngerman. 

The ideal candidate for MRgLITT is someone with focal-onset epilepsy that is not controlled with medications and whose seizures are believed to originate from the mesial temporal structures or other relatively small area. Doctors make an incision in the skull that is less than 1 centimeter long and guide a laser fiber to the area of interest. Heat from the laser removes the brain area generating seizures. During the ablation, temperature is monitored in real time using MR thermometry to prevent damage to the overlying cortex and white matter. “This allows us to preserve the vast majority of the brain while targeting just the area that we believe the seizures are coming from,” says Dr. Youngerman.

The results of a multicenter retrospective study were published in the Journal of Neurology, Neurosurgery & Psychiatry. Among a cohort of 268 patients across 11 comprehensive epilepsy centers, researchers found that approximately half of the patients remained seizure-free at their most recent follow-up, a period ranging from 12 to 95 months and with a median of four years. It’s the largest published series to date to examine the long-term outcomes of MRgLITT for temporal lobe epilepsy. Dr. Youngerman was the lead author on the study.

The results fall short of the 60% to 80% of patients who achieve seizure freedom with temporal lobectomy, but are close, Dr. Youngerman says. “This is still early data so the results may improve as we improve patient selection and targeting.” Patients can still opt for a traditional open surgical procedure if they continue to experience seizures.

Laser ablation is also being used to treat other types of epilepsy, such as cases caused by hypothalamic hamartoma, focal cortical dysplasia, and cavernous malformations.

Who's Who

• Iruma Bello, PhD, associate professor of clinical psychology (in psychiatry)
• Jeffrey Bruce, MD, the Edgar M. Housepian Professor of Neurological Surgery Research and a member of the Herbert Irving Comprehensive Cancer Center
• Peter Canoll, MD, PhD, professor of pathology & cell biology and neurosurgical sciences (in neurosurgery) and a member of the Herbert Irving Comprehensive Cancer Center
• Lisa Dixon, MD, professor of psychiatry
• Elisa Konofagou, PhD, the Robert and Margaret Hariri Professor of Biomedical Engineering, professor of radiology, and professor of neurological surgery and a member of the Herbert Irving Comprehensive Cancer Center. Dr. Konafagou received pilot funding from the Herbert Irving Comprehensive Cancer Center.
• J. John Mann, MD, the Paul Janssen Professor of Translational Neuroscience (in Psychiatry and in Radiology)
• John Markowitz, MD, professor of clinical psychiatry
• Guy McKhann, MD, professor of neurological surgery and a member of the Herbert Irving Comprehensive Cancer Center
• Ilana Nossel, MD, associate clinical professor of psychiatry 
• Jovana Pavisic, MD, assistant professor of pediatrics
• Peter Sims, PhD, associate professor of systems biology and a member of the Herbert Irving Comprehensive Cancer Center
• Luca Szalontay, MD, assistant professor of pediatrics
• Cheng-Chia Wu, MD, PhD, assistant professor of radiation oncology and a member of the Herbert Irving Comprehensive Cancer Center
• Brett Youngerman, MD, assistant professor of neurological surgery