Brain cancer—a devastating diagnosis in itself—can also be grimly swift in its prognosis. Even with surgery and chemo- and radiotherapy, patients with glioblastoma multiforme (GBM), the primary type of malignant brain tumor that affects 15,000 people in the United States annually, may survive only little over a year, and can suffer tumor recurrence in virtually the same brain region. Now, work combining the unique complementary skills of a neurosurgeon, a bioengineer, and a nanomedicine and stem cell expert has led to a new treatment for GBM that has shown great promise in animal studies. The Yale team reported on their breakthrough online on July 1 in the Proceedings of the National Academy of Sciences.
As leader of Yale Cancer Center (YCC)’s Brain Tumor Program, Joseph M. Piepmeier, M.D., Nixdorff-German Professor of Neurosurgery, has devoted years to patient care and research to combat GBM. Recently, he was involved in a clinical trial in which drugs were delivered in solution to tumors by pumping through catheters. “It was a wonderful idea, but it didn’t work,” Piepmeier says. “The liquid flowed away, into the spinal fluid or blood, and dissipated once we stopped infusion.” The delivery problem is central to treating any disease of the organ that is beyond the blood-brain barrier, which protects the sensitive brain tissue from circulating blood. It keeps out bacteria, but also prevents orally or intravenously delivered drugs from getting to where they are needed most, in the case of GBM.
Across campus, W. Mark Saltzman, Ph.D., chair and Goizueta Foundation Professor of Biomedical Engineering, had been developing biodegradable materials that could be loaded with chemotherapeutic drugs and placed in the brain after tumor surgery. Saltzman, also professor of cellular and molecular physiology and of chemical engineering, was one of the developers of the Gliadel wafer, a standard-of-care drug delivery system that can extend survival by some months in GBM. The presence of a structure or casing, like the wafer’s, is critical because it prevents drugs from dissipating into circulation or being metabolized too quickly. The device’s effects, however, are only modest, since drugs fail to diffuse from the wafer into the dense brain tissue. The solution, explains Saltzman, is an engineered nanoparticle about the size of a virus that encapsulates the drug and prevents it from being degraded.
With a well-designed vehicle, the highway into the brain was obvious: Piepmeier’s pump infusion system, known as convection-enhanced delivery, or CED. “Our innovation was to combine the two technologies,” says Saltzman. “CED can penetrate through tissue, and the nanoparticles control where the drug ends up and ensure its slow release.” The particles are small enough to reach interstitial spaces in the brain. Made of the same material as dissolving sutures, they do not aggregate, and eventually degrade.
A novel drug delivery system isn’t sufficient by itself in the case of GBM, however. The tumors tend to be infiltrative and particularly resistant to radiotherapy and drugs, in part because of something that wasn’t recognized until 2003: even solid tumors have what are called cancer stem cells. “These are the root of tumor development, and the reason we decided to do drug screening in this study,” says Jiangbing Zhou Ph.D., assistant professor of neurosurgery and biomedical engineering, who studied stem cells and drug screening at the Johns Hopkins University before joining the Yale faculty in 2011. To find the perfect passenger for the nanoparticle vehicle, Zhou screened nearly 2,000 compounds used in various products previously approved by the U.S. Food and Drug Administration. He was looking for anything that would kill or inhibit the self-renewal of brain cancer stem cells, the small fraction of GBM cells that are resistant, and can migrate to cause tumor recurrence. Zhou hit upon dithiazanine iodide (DI), a fungicide that was particularly lethal to brain cancer stem cells in culture.
Step by step, the researchers evaluated the penetration of nanoparticles in both healthy rats and rats grafted with a common tumor cell line. They also investigated how well the nanoparticle system diffused in the brain of a larger animal, a pig. The real test, however, was delivering nanoparticles loaded with DI to rats that had infiltrative tumors very similar to human GBM. Eight of 12 rats were cured. “Normally we don’t cure anybody, so this result is pretty great,” Piepmeier says.
Saltzman, Piepmeier, and colleagues are now preparing for a small human clinical trial, to take place at YCC next year. By monitoring patients with magnetic resonance imaging (MRI), they will be able to observe drug distribution and longevity after delivery. Evaluating the safety and efficacy of the nanoparticle delivery mechanism is critical, they say as is the selection of an optimal drug.
Saltzman commends Yale’s “remarkable environment” for enabling the kind of collaborative translational research that led to this new GBM treatment: “In most places, it is not easy for biomedical engineers to work this closely with clinical scientists. What we’ve done can only happen at a few special places, like Yale,” he says.