Novel Drug Delivery Systems Promise to Revolutionize Treatment of Inoperable Pediatric Brain Tumors
At NewYork-Presbyterian/Columbia University Irving Medical Center, experts in Pediatric Oncology, Radiation Oncology and Biomedical Engineering are collaborating on novel drug delivery methods that surmount the formidable hurdle posed by the blood-brain barrier to deliver focused therapies to inoperable pediatric brain tumors.
“Brain tumors are the leading cause of death in children with cancer, and children with newly diagnosed diffuse intrinsic pontine glioma (DIPG), glioblastoma and relapsed malignant brain tumors (medulloblastoma, ependymoma, high-grade glioma) have an extremely poor prognosis,” says Stergios Zacharoulis, MD, a pediatric neuro-oncologist at NewYork-Presbyterian/Columbia University Irving Medical Center who specializes in brain, spine and neural malignancies of childhood. “Despite recent advances in the treatment of adult cancers, we have failed to make significant progress in children with brain cancer. One important reason is difficulty penetrating the blood-brain barrier, which allows only a small percentage of the drugs administered as pills or by intravenous injection to reach the brain.”
“To address this problem, we are developing innovative approaches that precisely, safely and non-invasively cross the blood-brain barrier to focally deliver drugs to the tumor,” says Dr. Zacharoulis. “These approaches will enable oncologists to administer higher concentrations of drugs directly into the tumor, thereby minimizing the systemic side effects.”
One approach involves convection-enhanced delivery (CED) for the chronic infusion of medicine directly into the brain tumor under controlled pressure so that maximum drug diffusion is achieved. “Instead of one single injection, neurosurgeons implant under the skin a programmable drug-filled pump that has catheters expanding directly into the brain, allowing repeated chronic infusions and avoiding the systemic side effects of the medications,” explains Dr. Zacharoulis, who is developing the methodology in collaboration with Jeffrey N. Bruce, MD and the Neurosurgery team at NewYork-Presbyterian Columbia University Irving Medical Center. “This approach is particularly important for tumors that cannot be surgically removed, such as DIPG, glioblastoma and relapsed malignant brain tumors.”
Another benefit of the CED approach is drug diffusion that over longer distances inside the tumor. “A traditional injection diffuses medication into a small little shape within the tumor,” explains Dr. Zacharoulis. “In comparison, CED applies steady pressure to deliver a slowly expanding balloon of medication, which allows us to achieve higher intra-tumoral drug concentrations.”
“We are about to open the first in the world study using the CED device with a pump that is placed under the skin and catheters connected to the brain stem allowing CED with pulsatile infusions of water-soluble Panobinostat (MTX110), a histone deacetylase inhibitor for children with DIPG,” says Dr. Zacharoulis. “The goal of this study is to establish the safe dose of MTX110 given with the CED device.”
In another project, Dr. Zacharoulis is investigating a device that employs dynamic ultrasound (FUS) in combination with intravenously injected microbubbles to gently separate the cells of the blood-brain barrier, allowing therapies to reach the brain tumor. “We have performed extensive laboratory studies in primates showing that the blood-brain barrier can open and allow significantly higher amounts of drugs into the tumor,” says Dr. Zacharoulis, who is working on the device in collaboration with Cheng-Chia Wu, MD, PhD, Radiation Oncologist at NewYork-Presbyterian Columbia University Irving Medical Center and Elisa Konofagou, PhD, Professor of Biomedical Engineering at Columbia University. “Although other groups have tried similar work, their devices require surgical implantation, whereas our team’s device is non-invasive.”
Dr. Zacharoulis believes the FUS with microbubbles approach has the potential to be used to treat children with any type of recurrent malignant brain tumors. “We are in the process of opening a proof-of-concept study in children with recurrent malignant tumors that will have a surgical resection,” he says. “One day prior to surgery, these patients will have FUS followed by administration of intravenous drugs and serial imaging following by surgical resection in which the tumor concentration of the drug will be measured. This is the first-ever study of this device in children with brain tumors.”
Dr. Zacharoulis envisions a future in which both of these innovative drug delivery systems will transform the existing therapeutic armamentarium toward much more effective and less toxic treatment options. “If we can demonstrate that these drug delivery methods can successfully penetrate the blood-brain barrier, we could use lower dosages to effectively treat pediatric brain tumors, and patients would endure fewer side effects, thereby changing the paradigm of how we treat pediatric brain tumors,” he says. “Eliminating the obstacle posed by the blood-brain barrier also opens the door to the discovery of new medications and the repurposing of old ones that we had thought didn’t work, which only increases the therapeutic options in our arsenal.”
“The development of these approaches requires the interdisciplinary collaboration of so many specialists, technicians, scientists, and clinicians,” he adds. “It is so exciting to be part of these initiatives that may one day change the current dire predictions that come with a pediatric brain tumor diagnosis.”
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