In children, a projected 3,540 new pediatric brain tumors will cause suffering for patients and their families each year. Pediatric brain tumors are the leading cause of cancer-related deaths in those under 19 years of age. (Source for statistics: National Brain Tumor Society Brain Tumor Facts)
There has been minimal improvement and, with no definitive cure for brain tumors, the mortality rates over the last 30 years are relatively unchanged. There are still only five FDA approved drugs and one approved medical device to combat the most malignant brain tumors. Existing medications likely do not reach brain tumors in high enough concentrations – due to the presence of the blood-brain barrier (BBB) – and these medications may not be effective in killing the tumor cells even if they reach the tumor in sufficient concentrations. New approaches are critical to change the outcomes for these patients.
Focused ultrasound has shown the potential to be the game-changing new approach that is needed. This technology noninvasively attacks brain tumors in a variety of different ways – from tissue ablation to enhanced delivery of various neuro-therapeutics. The enthusiasm of the focused ultrasound scientific community is apparent by the current volume of technical, preclinical, and clinical research projects in this area.
Brain Technical Studies
The Foundation is invested in improving the complex technology of focused ultrasound to make treatments safer and more effective. There are many ongoing technical projects involving the brain that hope to accomplish this goal. John Snell, the Foundation’s Technical Director, created Kranion®, an open-source, interactive transcranial focused ultrasound visualization system. He continues to develop this platform, which helps with brain treatment planning. Additional brain technical projects aim to improve different aspects of treatment planning and monitoring, and these include tractography, advanced MRI techniques, and improved temperature mapping technologies.
Preclinical Studies
There are many preclinical research projects involving brain tumors and focused ultrasound, and several of these are being funded by the Focused Ultrasound Foundation.
Researchers are combining focused ultrasound with other agents and treatment modalities to evaluate the effect of combination therapies in the management of brain tumors. For example, investigators at the University of Virginia (UVA) are exploring the use of focused ultrasound combined with microbubble injection to disrupt blood vessels within brain tumors, which cuts off the blood supply to tumor cells and leads to cell death. Another study at UVA combines radiation with focused ultrasound in the treatment of gliomas. Yet another team of researchers at UVA recently completed promising studies involving sonodynamic therapy, which combines fluorescent dyes (5-ALA and fluorescein) with focused ultrasound for the treatment of brain tumors.
There are numerous preclinical laboratory studies assessing focused ultrasound’s role in immunomodulation and immunotherapy for brain tumors, both primary and metastatic. The focused ultrasound community is awaiting the publication of the results of a multisite consortium, which assessed immune cell populations after different types of focused ultrasound in a mouse glioma model. There is also an ongoing investigation into the optimal timing of focused ultrasound and immunotherapy for the treatment of brain tumors.
In addition to preclinical work on primary malignant brain tumors, studies are also looking at focused ultrasound for benign brain tumors and metastatic brain tumors. A cerebral cavernous malformation (CCM) is a collection of small blood vessels in the brain that is enlarged and irregular. A preclinical study at UVA is examining the treatment of CCMs with focused ultrasound in combination with 5-ALA. Another study, also at UVA, aims to enhance immune therapy for brain metastases using focused ultrasound.
Investigators at the University of Michigan are currently examining the safety and feasibility of histotripsy to treat brain tissue. Histotripsy uses focused ultrasound to mechanically destruct tissue rather than using heat to destroy tissue. This advancement in science may make focused ultrasound even safer, as it has been shown to spare critical structures around the target such as blood vessels and bone.
Clinical Trials
Clinical trials involving focused ultrasound have been recruiting patients from children to adults of all ages, with either benign or malignant brain tumors, including both de novo and recurring tumors. Various focused ultrasound devices provide unique approaches: Some are using imaging guidance while inside the MRI scanner (Insightec), and others are guided by neuronavigation from a previously performed MRI or CT scan (NaviFUS). Another manufacturer does not rely on imaging guidance but rather implants an ultrasound transducer into the skull directly over the target area after surgical resection (CarThera).
For glioblastomas (GBMs), focused ultrasound studies are opening the BBB to deliver increased concentrations of either chemotherapy or immunotherapies directly to the tumor and its surrounding tissues (where most recurrences take place). Some of these studies administer the chemotherapy agents preoperatively to then study the pharmacokinetics of drug delivery to the tumor specimen. Other trials open the BBB during maintenance chemotherapy or after tumor recurrences in multiple sessions over several months.
As mentioned in the preclinical research section above, sonodynamic therapy is another approach to treating GBMs. After an innocuous dye such as 5-ALA accumulates in tumor cells, focused ultrasound is targeted to the tumor where it activates the 5- ALA, which then causes cell death. The Foundation has established a steering committee to lead an international effort to perform translational work with sonodynamic therapy. We expect clinical studies to begin in early 2021.
The first in-human study to increase BBB permeability and deliver targeted therapies to brain metastases has already recruited patients in Canada. This first application is to deliver the immunotherapy drug Herceptin to patients with metastatic HER2+ breast cancer. Using focused ultrasound to deliver other therapeutics to melanoma and lung metastases in the brain will likely begin soon.
Researchers are optimistic about the potential benefit that focused ultrasound will have for the pediatric brain tumor population, as it may provide an alternative to invasive brain surgery that can be associated with significant short- and long-term complications. Focused ultrasound may also improve directed therapies to tumors that are otherwise not amenable to surgery due to location of the tumor (too deep in the brain or involving eloquent areas). One pediatric clinical trial uses focused ultrasound to thermally ablate benign tumors (e.g., hypothalamic hamartomas). Although these tumors are benign, they can cause symptoms such as epilepsy and cognitive delay, so a noninvasive treatment option is attractive. Clinical trials are also scheduled to begin treating various pediatric malignant brain tumors such as medulloblastomas, ependymomas, midbrain gliomas, and diffuse intrapontine gliomas with focused ultrasound opening of the BBB to increase drug delivery.
Liquid Biopsies for Brain Tumors
Another interesting avenue of research gaining the attention of the neurosurgical community involves using focused ultrasound to increase the yield of liquid biopsies for brain tumors. Liquid biopsies are an emerging application used to diagnose and follow the progression of patients with cancer in many areas of the body. However, liquid biopsies for brain tumors have not yielded consistent results compared to cancers outside the brain, likely due to the BBB. The tightly aligned BBB cells along the vessels in the brain that can prevent drugs from getting into the brain likely also prevent genetic material from brain tumors to travel back into the peripheral circulation.
A recent preclinical study detected a significant elevation of brain tumor RNA after focused ultrasound was used to open the BBB. The poor survival of patients with malignant brain tumors involves the marked heterogeneity of the tumor and its ability to mutate over time, becoming resistant to conventional therapies. Thus, opening the BBB in various regions within the brain tumors may provide a more comprehensive window into the tumor and allow for more targeted, precision medicine unique to the patient’s tumor characteristics. The Foundation is currently evaluating various abstracts to fund such projects in clinical trials.
Brain Tumor Awareness Month
Each year, the month of May is designated as Brain Tumor Awareness Month, and the Focused Ultrasound Foundation wants everyone to know that we are actively engaged in making a difference in the lives of those impacted by brain tumors. We believe that focused ultrasound is a technology that can drastically change the treatment landscape for people living with brain tumors, improving both their quality and longevity of life. We will continue to solicit and support preclinical research and clinical trials, in addition to building relationships with organizations such as the Cancer Research Institute (CRI) to support our mission.
Finally, a Quick Read
John Grisham, a member of our Board of Directors, is a fervent supporter of the Foundation and our passion to improve treatment options and outcomes for patients with brain tumors. A few years ago, John wrote a book called “The Tumor” which followed a fictitious patient with a malignant brain tumor whose outcome was improved due to focused ultrasound. More than 1 million copies of the book have been distributed to date. Find out more and download your free copy.
Additional Resources
Treating Senator John McCain: Can Focused Ultrasound Help Patients with Glioblastoma and Other Brain Tumors?
Glioblastoma Multiforme: Tragedy and Hope for the Cancer that Killed Senator John McCain
Overview of Focused Ultrasound for Brain Tumors
Brain Metastases Workshop
Immunotherapy for Brain Tumors Webinar
Suzanne LeBlang, MD, is the Director of Clinical Relationships at the Focused Ultrasound Foundation.
Lauren Powlovich, MD, is the Director of Special Projects at the Focused Ultrasound Foundation.