M. D. Anderson: Setting The Benchmark In Brain Tumor Treatme

M. D. Anderson: Setting the Benchmark in Brain Tumor Treatment
Promising chemo, therapeutic viruses, cutting-edge surgery debut at Brain Tumor Center

Brain tumor specialists at The University of Texas M. D. Anderson Cancer Center are poised on the brink of a new era.

The molecular revolution that has led to improvements in treating other cancer types is well under way at the institute's Brain Tumor Center. For the first time in decades, new therapies are bringing hope to patients and physicians. And at long last, glioblastoma, the most common and deadly of brain tumors, is finally giving up some secrets.

Encouraged by the finding that a new chemotherapy drug works best in patients who have no expression of a specific genetic alteration, researchers at the Brain Tumor Center are leading the U.S. arm of a worldwide study that aims to characterize as many as 20,000 genes and proteins that may play a role in brain tumor development.

They have other reasons to be optimistic. A vaccine that tricks the immune system into attacking a protein found on glioblastoma cells is showing promise in patients treated at the Brain Tumor Center. 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. Another trial is studying a chemotherapy drug that can seep through the brain-blood barrier and latch on to tumor cells. All of these experimental approaches were developed at M. D. Anderson. Some have the backing of the National Cancer Institute as well as the interest of pharmaceutical companies.

Traditional brain tumor therapies also are being refined at the Brain Tumor Center with this next-generation technology that will offer safer, more precise treatment. A proton synchrotron particle accelerator will be online in 2006 to offer some brain tumor patients the most precise radiation therapy available, as will a new suite of neurosurgical devices featuring real-time imaging that surgeons can use to navigate inside the brain.

While the co-directors of the Brain Tumor Center are energized about the future, they also are realistic. The finest surgery, medical and radiation treatments are not enough, they say. Next-generation drugs must be developed to change the forecast for most glioblastoma patients. The road to developing a fleet of agents designed to disarm the numerous pathways brain tumors use to thrive will surely be a bumpy one.

"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 prefect many different avenues for treatment, and hit the right combination of multiple drugs and therapies that works best for each individual patient."

"We are just now on the cusp of understanding much more about the molecular biology of the disease," says W. K. Alfred Yung, M.D., professor and chair of the Department of Neuro-oncology. "What we are learning right now can only improve our ability to treat each tumor, and each patient."

Reading the molecular signature
Hunt for genes springs from chemotherapy success

For the first time, there is a chink in the armor of one of the most deadly human tumors. The chemotherapy drug Temodar (temozolomide), first tested by M. D. Anderson researchers in recurrent glioblastoma and approved for use in those tumors last year, bumps up the life span in some patients by a number of months. A few who participated in early clinical testing of the drug are alive years beyond what was expected.

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 (0-6-methylguanine-DNA methyltransferase or MGMT) that remains silent during treatment. Temodar does not help patients with an active, efficient MGMT gene - 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 neuro-oncologist Mark Gilbert, M.D. "Temodar is the first new brain tumor treatment 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, testing 840 glioblastoma patients to see whether increasing doses of the drug will overcome the repair gene problem.

"This kind of collaboration is exciting, and it is unprecedented, not only in brain tumor research but in cancer research across the board," says Gilbert, the study's principal investigator. "I think the entire cancer community is recognizing that the whole is greater than the sum of the parts."

The study, which has recently begun enrolling patients in some sites, also aims to collect uniform tumor samples from every participant, another first, Gilbert says. "In the past, institutions have differed in the way they collect such samples, which means these samples are hard to compare to each other," he says. "For the first time, all centers participating in this trial will be collecting them in a uniform way so that we can study all samples and put the information we find into a comprehensive database."

The tissue will be examined for its MGMT status, which will then be correlated with outcome for each patient. These tissue samples will be further studied to determine the genes and proteins that are switched on at the time the biopsy was taken. Such information will help identify the molecular pathways that cancer cells use to override normal growth controls.

In the United States, all samples will be sent to Ken Aldape, M.D., at the Brain Tumor Center at M. D. Anderson. "Normally, molecular profiling is done on samples of convenience - on whatever you can find in your laboratory freezer - and so that kind of analysis has not told us that much," says Aldape, lead U.S. pathologist for the trial. "This is an unprecedented effort to understand precisely what is going on in brain tumors."

Gilbert says that up to 20,000 genes and proteins can be characterized through this screening process, and the results will be compared to the dozen different pathways known to be active in many cancers. Among the more common genetic alterations seen in malignant brain tumors are: the p53 tumor suppressor gene, EGFR genes that control cell growth, PDGF and VEGF genes involved in cell growth and angiogenesis and the MMAC/PTEN tumor suppressor gene.

"In the last ten years, we have learned an amazing amount about all the different pathways glioma cells use," says neurosurgeon Frederick Lang, M.D. "These tumor cells are very smart, they mutate rapidly, they have a lot of fallback pathways and we haven't found an Achilles' heel yet."

Still, Aldape says that this gene screening may identify new pathways. With the molecular profiles in hand, researchers may then begin to rationally analyze targeted therapies that have a chance of working on malignant brain tumors, including those for which Temodar has not worked. Agents are approved or are being developed that work in each of these pathways, Gilbert says.

"The dream in the field is that the molecular profile of the patient's tumor will drive the treatment and that we can quickly test a number of different combined drugs against the particular tumor, which is the essence of individualized treatment," he says.

Researchers at the Brain Tumor Center are the first to point out that use of a single targeted therapy has not worked well so far to fix errant pathways. A trial of a gene therapy vector to replace the p53 gene missing in most brain tumors failed, as did an attempt to use a drug that blocks over-expression of EGFR, which is amplified in about 60 percent of glioblastomas. Single agent tests of other targeted therapies, such as platelet-derived growth factor (PDGF) and Ras inhibitors, have not worked. Gleevec, which has revolutionized the treatment of chronic myelogenous leukemia, was first tested in brain tumors to little effect.

Gilbert predicts that years will pass before testing of combined agents is routine. Drug testing guidelines are not yet flexible enough to allow clinicians to test approved agents with experimental therapies, he says, and issues will pop up as to who owns a winning drug combination. Still, Gilbert adds, "It is great to have the world working together."

Novel viruses and Trojan horses
NCI endorses testing a smart virus

A different and completely novel approach - a "viral smart bomb" - that was developed at the Brain Tumor Center is designed to go after cancers cells and spare normal cells based on differences in the molecular makeup of cancer cells and normal cells.

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 in the fall of 2006.

The therapy, known as Delta-24-RGD, is a new-generation "replication-competent oncolytic" adenovirus therapy. It is a therapeutic virus that spreads, wavelike, throughout a tumor, infecting and killing cancer cells along the infiltrative fingers of brain tumors, but that does not affect normal cells. (责任编辑：泉水)

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M. D. Anderson: Setting The Benchmark In Brain Tumor Treatme