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Return to Surgeon Develops New Treatments for Glioblastoma Overview

More on Surgeon Develops New Treatments for Glioblastoma

Surgeon Develops New Treatments for Glioblastoma

New York, NY (Sep 25, 2009)

Dr. Jeffrey Bruce
Dr. Jeffrey Bruce

Glioblastoma is both the most common and most deadly type of malignant brain tumor. "With no treatment these tumors are fatal in a matter of a couple of months," said NewYork-Presbyterian Hospital neurosurgeon Dr. Jeffrey Bruce. "With a skillful surgery, radiation, and chemotherapy patients can live to a year, or even more." Current standard therapy includes surgery to reduce the tumor, radiotherapy, and temozolomide both during and six months post radiotherapy. Researchers at many institutions are working toward more effective treatments for glioma. At NewYork-Presbyterian Hospital Dr. Bruce and colleagues are approaching gliomas on three fronts.

New Mode of Delivery

Dr. Bruce recently completed a phase I trial of a novel delivery system for the topoisomerase inhibitor topotecan, and is launching a multi-institutional phase II trial of this treatment approach. Using a concept called convection-enhanced delivery, surgeons implant one or more catheters into the tumor and the surrounding brain. Over four days topotecan is slowly pumped directly into the tumor and surrounding tissue.

Illustration of human head and brain

With intravenous or oral delivery of chemotherapy, the drug distributes itself along a concentration gradient until it reaches a uniform concentration throughout the body, Dr. Bruce explained. In convection delivery the agent flows through the fluid filling the interstitial space, "almost like a river streaming away from the catheter into the surrounding brain," he said. "The brain itself is sponge-like, and when you infuse topotecan it basically displaces the water, and then crosses through the cell membrane."

Because convention enhanced delivery is done so slowly the agent can accumulate in very high concentrations in the brain, allowing physicians to achieve drug levels more than a thousand-fold greater than is possible with intravenous delivery, said Dr. Bruce. Since topotecan is a topoisomerase inhibitor, it affects only multiplying cells such as those in tumors and does not create any additional side effects.

Identifying Progenitor Cells

In a second area of research Dr. Bruce is working with NewYork-Presbyterian Hospital pathologist Dr. Peter Canoll to identify glial progenitor cells in an effort to determine the origin of brain tumors. Progenitor cells, found throughout the white matter, appear to be the "seeds" of gliomas, he said. Dr. Bruce explained that, like glioma cells, progenitor cells are migratory and invasive; they have a diverse progeny; they divide and proliferate. They have a relationship with both blood vessels and white matter and tend to travel along the same tracts in the brain; and they can express a number of immature genotypes – growth factor-related genes and oncogenes are highly expressed in these types of cells, he said.

"The idea of a stem-like cell causing a tumor has become a popular theory in the evolution of brain tumors," said Dr. Bruce. "If we can understand the molecular and genetic differences between the cells that cause tumors versus normal brain cells we may be able to develop treatments that target the particular characteristics of the deadlier forms of tumor cells."

Immune-based Therapies

The immune system recognizes many types of cancer as foreign and mounts a response to them, but these responses are not often very strong, and in the case of glioma the tumor grows faster than the immune system can eradicate it. "We've found that as a tumor grows it actively secretes cytokines that block immune responses," he said. "In glioblastomas in particular there's a lot of work showing that the microenvironment where the tumor is growing is a very immunosuppressive one."

Members of Dr. Bruce's lab including Dr. Richard Anderson as well as colleagues at University of California San Francisco are studying the types of immune cells that respond to tumors and the factors that bring them to the tumor site, as well as the factors released by the tumor to block the immune response. The team is about to start a trial in recurrent glioma in which they will test a vaccine derived from the patient's own tumor cells. Tumor proteins that provoke an immune response are isolated and amplified, and used as the basis of the vaccine. Patients will receive the vaccine by injection every week for several weeks.

Dr. Bruce has conducted animal studies in which an experimental glioma is implanted under the skin of a rat, and the rat is treated with a vaccine made of abnormal proteins in the tumor. "Over time the animals mount a massive inflammatory response to the tumor and eradicate the tumor cells. So this kind of strategy actually works in an experimental setting," he said. "We hope to one day have similar success in patients with brain tumors."

Contributing faculty for this article:

Jeffrey N. Bruce, MD is the Director of the Bartoli Brain Tumor Research Laboratory and a Co-Director of the Brain Tumor Center at NewYork-Presbyterian Hospital/Columbia University Medical Center. He is also the Edgar M. Housepian Professor of Neurological Surgery at Columbia University College of Physicians and Surgeons.

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