New Benchmarks in Brain Tumor Treatment
Network - Winter 2007
Brain tumors differ from tumors that occur elsewhere in the body:
- They are highly variable with more than 125 known kinds.
- They are hard to see because the majority are not encased, like those that occur in the breast and some other organs.
- They are difficult to remove, because the tumors’ long fingers, which reach from a central body to burrow deep into brain matter, can’t be easily distinguished from normal brain tissue.
- And malignant brain tumors, especially the common glioblastoma, are highly resistant
Delivery of a drug also is problematic because the tumor usually is enclosed in a tight quarter in the brain, which is itself protected by a blood brain barrier. And radiation therapy is tricky because of the risk treatment poses to brain tissue caught in the X-ray beam.
To address these difficulties, M. D. Anderson created the Brain Tumor Center in mid-2001. A resource like none other in the world, it is a “virtual” place where 78 faculty members are exclusively dedicated to the care and study of brain tumors.
The researchers and clinicians who work at the center say that only an all-out team effort will succeed in improving care and treatment of brain tumors, a disease so resistant to therapy that the survival rate has remained the same for many years. For patients with glioblastoma, the most common and the most destructive kind of brain tumor, life span after diagnosis is a matter of months with no treatment, and an average of one year following surgery and radiation, says M. D. Anderson neuro-oncologist, Alfred Yung, M.D., the center’s co-director.
“There will be no magic bullet to treat brain cancer,” says Raymond Sawaya, M.D., professor and chair of the Department of Neurosurgery. “The answer is not going to come from one approach. We have to test and perfect many different avenues for treatment, and hit the right combination of multiple drugs and therapies that works best for each individual patient.”
Chemotherapy breakthrough increases patient life span
Researchers know that resistance to Temodar occurs in many patients. They also now understand that patients who initially respond to it have a specific DNA repair gene that remains silent during treatment. Temodar does not help patients in whom this gene is active because their cancer cells are being mended as fast as the drug can injure them.
A test may soon be available to pinpoint patients best served by Temodar. This first baby step toward individualized therapy for brain tumors constitutes a huge moment in the study and treatment of aggressive brain tumors.
Uncovering this one secret in the molecular doings of glioblastoma has bolstered the spirits of brain tumor researchers and clinicians worldwide, says Mark Gilbert, M.D., associate professor in the Department of Neuro-Oncology. “Temodar is the first new brain tumor drug approved for use in the last 20 years, and the fact that it works better in some patients has energized the field.”
Researchers from the United States, Europe and Canada are now collaborating on the largest brain tumor clinical trial ever undertaken, he says. They have launched a phase III test of Temodar among 840 glioblastoma patients to see if increasing doses of the drug will overcome the repair gene problem.
A ‘viral smart bomb’ may spare normal tissue
A clinical trial is soon to open on a virus designed to spread rapidly through the extended fingers of a brain tumor, killing it while leaving normal tissue alone. This novel approach, a “viral smart bomb,” is designed to go after cancer cells and spare normal cells based on differences in their molecular makeup.
It is considered so promising that the National Cancer Institute is producing a drug-grade version of the virus, and a clinical trial is slated to begin soon.
The therapy, known as Delta-24-RGD, is a new-generation adenovirus therapy — a therapeutic virus that spreads wavelike throughout a tumor, infecting and killing cancer cells along the infiltrative fingers of brain tumors — that does not affect normal cells.
In mice, the treatment completely eradicated gliomas, a “response that has never been seen before,” says Juan Fueyo, M.D., associate professor in the Department of Neuro-Oncology and the researcher who developed the treatment. The mice were considered clinically cured of their brain tumors, and in examinations, researchers found only empty cavities and scar tissue where the tumors had once been.
“Cancer is devious, but this virus is equally tricky,” says Frederick Lang, M.D., professor in the Department of Neurosurgery and the neurosurgeon who will help conduct the trial with Charles Conrad, M.D., associate professor in the Department of Neuro-Oncology. Lang will insert a catheter into participants’ brain tumors, inject Delta-24-RGD and wait two weeks to surgically remove the malignancy. The tumor will then be examined to see how much of it has been destroyed.
A vaccine that tricks the immune system
Researchers have other reasons to be optimistic. A vaccine that tricks the immune system into attacking a protein found on glioblastoma cells also is showing promise. Neurosurgeon and researcher Amy Heimberger, M.D., is focusing on the power of immunity to help keep a brain tumor at bay. So far, the phase II clinical trial she leads is significantly increasing the expected life span of enrolled patients.
Along with investigators at Duke University Medical Center, Heimberger designed a vaccine that alerts the immune system in the brain to the presence of just one type of protein that studs the outside of a glioma. In fact, the protein, epidermal growth factor variant III (EGFRvIII), is found on brain tumors, as well as on breast and non-small cell lung cancers. Heimberger believes it drives gliomas to spread, explaining why they are unusually dangerous and invasive.
Patients at M. D. Anderson and at Duke whose brain tumors, once removed, show evidence of the protein are eligible for treatment with the vaccine, which contains a synthesized piece of the protein and a stimulator for the patient’s dendritic cells that activate the immune system.
The research team examined the first 23 patients enrolled in the 44-patient trial and found that it took the tumors significantly longer than is typical to come back. When the recurring tumors were removed, there was no longer any evidence of the EGFRvIII protein on the new glioma, an indication that the vaccine worked, but that the tumor morphed to use a different pathway to grow again. Median survival among the treated patients also was significantly longer, at least 18 months.
Heimberger says that if the vaccine continues to prove beneficial in future testing, it probably should be combined with chemotherapy treatment. New findings show the chemotherapy can change tumor cells so they are more susceptible to destruction by the immune system.
“This is exciting to us because people have been trying to use immunotherapy against gliomas for a long time,” she says. “We need to find ways so that these therapies can work together synergistically.” She adds that the vaccine could potentially be used for breast and lung cancers, and a trial has been opened at the University of Washington to test this hypothesis.
Working side by side, the Brain Tumor Center team has been able to offer more clinical studies to their patients than any other institute. The more than 1,400 new patients treated here every year, as well as thousands of returning patients, are often first to be offered new therapies, some of which were exclusively developed in M. D. Anderson laboratories or were first tested at the Brain Tumor Center.