A New Paradigm for Brain Tumors

The brain is shielded from most toxins and pathogens by a highly complex network of blood vessels—the blood-brain barrier—that restricts the size and chemical composition of molecules that can cross vessel walls into brain tissue. This barrier is also one of the major challenges neuro-oncologists face in treating brain tumors: most chemotherapeutic agents are not able to pass through the blood-brain barrier to reach brain and spinal cord tumors, or do so only in very low and ineffective amounts. For decades researchers have tested new agents in both pediatric and adult brain tumors with little success, “and there is tremendous room for improvement,” says Columbia pediatric neuro-oncologist Stergios Zacharoulis, MD. 

In the coming months Dr. Zacharoulis and colleagues from Columbia University will launch several new clinical trials, some testing ways to circumvent the blood-brain barrier, others precision therapy studies to ascertain which drugs will be most effective again each patient’s tumor. Through this research Dr. Zacharoulis hopes to impact the currently dismal outlook for the 4,000 children in the US diagnosed each year with a brain or spinal cord tumor. 

Along with a team that includes neurosurgeons Neil Feldstein, MD and Jeffrey Bruce MD, and pediatric oncologist James Garvin, MD, Dr. Zacharoulis will soon open a clinical trial of a new approach for children with the highly aggressive brainstem tumor, diffuse intrinsic pontine glioma (DIPG). In this study the neurosurgeons will insert several tiny catheters directly into the tumor. A small device implanted under the skin will gradually pump the best-available drug (panobinostat, a histone deacetylase inhibitor), into the malignancy, enabling the researchers to treat the tumor directly and continuously over two days. Because the Columbia team is the first in the world to use this device with this new drug, “the study is generating a lot of excitement in the community,” Dr. Zacharoulis says. 

With researchers from Columbia’s biomedical engineering department (Elisa Konofagou, PhD and Antonios Pouliopoulos, PhD) and radiation oncology department (Cheng-Chia Wu, MD, PhD), he plans to test a noninvasive approach that will allow higher concentrations of drugs to enter the brain by opening the blood-brain barrier using focused ultrasound with microbubbles. These miniscule gas-filled spheres are responsive to ultrasound and, when they're activated they mechanically separate the cells lining the vessel walls. While researchers have used ultrasound in the past, this study will be the first in the world to assess this new, non-invasive technique, says Dr. Zacharoulis. “We hope to show that, using smaller doses of an active drug, we can achieve the same, or even better results, and avoid the systemic side effects for these children.” 

Through a precision therapy study Dr. Zacharoulis and colleagues will use freshly operated tumor tissue and test it for its responsiveness to various concentrations and combinations of biologic and chemotherapeutic drugs. They will analyze treated and untreated tumor samples using advanced sequencing tools to learn which drugs are active, and what to do to prevent further relapse. “This is practically a virtual, ongoing biopsy,” he says. In addition, the results of this analysis will be available in three days, often before results are available from the pathology lab.

Since the late 2000s the number of pediatric brain and spinal tumors has been on a slight but steady uptick, and these often deadly diseases are on course to overtake leukemia as the most common cancers in children. Through research based on new technologies and new drugs Dr. Zacharoulis is determined to provide children with these tumors a brighter future.