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Glioma: Studies Offer New Drug Targets

Whitlock, Kelli

doi: 10.1097/01.COT.0000294689.53917.e5

Studies of the molecular underpinnings of the most aggressive type of glioma, glioblastoma multiforme, have revealed promising targets for drug therapy, information that also offers insight into what causes these brain tumors to form and grow.

Gliomas are the most common form of primary brain tumor and the second most common cause of cancer deaths between the ages of 15 and 44. Patients with glioblastoma multiforme (GBM) often have a life expectancy of one year or less. Current treatment may include surgery, chemotherapy, radiation, or a combination.

Scientists once thought the molecular structure of glioblastomas was so patient-specific that identifying drug targets on the cancer cells would prove difficult.

“The dogma was that it was impossible to find anything common among more than 50% of patients with GBM,” said Waldemar Debinski, MD, PhD, Director of the Brain Tumor Center of Excellence at Wake Forest University Medical Center, whose work disproved that conventional wisdom.

In his latest studies, presented at meetings of the World Federation of NeuroOncology and the European Association for NeuroOncology, Dr. Debinski identified a protein involved with tumor malignancy, another protein that plays a role in cancer growth, and a group of proteins that work on a molecule involved in immune system function.

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Cytokines Increase Level of Drug Target Receptors

About 10 years ago, Dr. Debinski, then at Pennsylvania State University, discovered that GBM cells have a specific receptor for interleukin 13 (IL-13), a naturally occurring immune-system regulatory protein.

Studies suggest that IL-13 is present in about 70% of GBMs, and since healthy cells lack this receptor, it made a good therapeutic target for novel drugs. Neopharm, a biotechnology company that is developing a drug based on Dr. Debinski's research, is conducting Phase III trials of the drug, which has been granted Fast Track status by the FDA.

In these new studies, Dr. Debinski found that, in cell culture, cytokines regulate the expression of IL-13 receptors, or in the case of brain tumor patients, the overexpression of the receptors. Scientists now are interested in learning more about how the cytokines might be incorporated into a therapeutic regimen.



“We're looking for ways to increase the number of receptors on cancer cells,” Dr. Debinski said. One possibility, he suggested, is to “prime the tumors with cytokines, for up to 24 hours, and then add the cytotoxin.”

The researchers tried this technique in their studies and demonstrated that this short-term pretreatment increased the number of IL-13 receptors, which could increase the effectiveness of the drug now in clinical trials.

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Protein Identified as Drug Target

Dr. Debinski also presented findings on another new study of EphA2, a tyrosine-kinase receptor involved in neural development. EphA2 is expressed at low levels on the surface of healthy cells, but in certain types of cancer, including breast, colon, prostate, and ovarian, EphA2 is overexpressed. The thought is that in cancer cells, EphA2 plays a role in angiogenesis.

To see what role, if any, EphA2 plays in glioblastoma multiforme cells, Dr. Debinski designed a study to examine the protein's activity in healthy brain tissues and GBM cells. Genotyping revealed high levels of EphA2 in GBM tissue. What's more, the researchers also found that if they added the ligand Ephrin-A1, a small molecule that binds to EphA2 on the cell surface, the GBM cells lost some of their cancerous properties.

“Ephrin-A1 caused glioma cells to be less active in forming colonies in an assay that reflects their tumorigenic potential,” Dr. Debinski said. “Thus, activating the EphA2 receptor may slow or stop tumor growth. EphA2 is expressed in so many glioma samples that detecting it may help in the diagnosis of tumors.”

Learning how such molecules behave in normal tissue is an important step toward understanding what happens with the molecules in diseased tissue, said Michael Berens, PhD, Senior Investigator at the Translational Genomics Research Institute in Phoenix, who studies Ephrin-B2 and other members of the ephrin family of molecules, which includes EphA2. Ephrins are among the cell's largest groups of signaling molecules and are unique because of their capacity for two-way communication.

“EphA2 and Ephrin-B2 are both receptors and transmembrane proteins that communicate signals from the outside to the inside of the cell,” Dr. Berens said.

“The ligand that activates that receptor characteristically is also bolted to an adjacent cell. The Ephrin receptor-ligand family signals in both directions, telling the cell that, ‘Hey, I found somebody that's meaningful to us.’”

That makes ephrins very attractive drug targets, Dr. Berens suggests, as well as good vehicles for learning more about how gliomas grow and spread.

“Unlike breast or colon or prostate cancers—which are all very destructive—the invasive behavior of gliomas takes a very benign appearance. You really can't figure out how so many cancer cells got so far away from the mass. The ephrans are going to help us understand how this gentle, malignant invasion takes place by offering us more information about signaling between cancer cells.”

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Protein Involved in Tumor Malignancy

In the third study, Dr. Debinski and his colleagues were examining how tumors develop their own blood supply when they came across a transcription factor called Fra-1, a protein highly overexpressed in cancer cells that seemed to regulate transcription of as many as 50 different genes.

When Fra-1 was added to non-cancerous cells, the cells began producing tumors. But when the protein was removed from tumor-producing cells, the cells lost their cancer-making capabilities. The research, which was done in mice, was published in Molecular Cancer Research (2005;3:237–249).

“We didn't suspect that Fra-1 is such a powerful biological factor, but it looks like it is a potent regulator of glioma cells'; morphology,” Dr. Debinski said. “When you add a little more of this factor, the cells start to assume a very different shape. Excess of Fra-1 makes them more elongated, slimmer and with a larger number and longer cellular processes. Diminishing Fra-1 brings about the opposite.”

Fra-1 is overexpressed in 60% of the tumors Dr. Debinski studied. An excess of Fra-1 is also found in other cancers, including colon, thyroid, skin, and breast. In fact, he noted, a French research team recently published findings from a breast cancer study that indicate that Fra-1 is involved in cell proliferation and mobility.

Dr. Debinski's studies suggest that to do its work, Fra-1 joins with nearby molecules. If Fra-1 proves a difficult target for drug development, one of its partner molecules may be a better candidate.

“It's always good to target the molecule that not only has a high expression level but also has a crucial biological role,” said Hideho Okada, MD, PhD, Assistant Professor of Neurosurgery and Surgery at the University of Pittsburgh Medical Center.

Dr. Okada will be participating in a clinical trial to study drugs designed to target three molecules, including EphA2 and the IL-13 receptor. “We still need to find out if Fra-1 has an immunological motive,” he said. “A high expression of a protein or antigen doesn't necessarily mean that protein or antigen is immunogenic.”

Still, Fra-1's role as a transcription factor increases the likelihood that it may have a causal role in cancer development, suggests Eric Holland, MD, PhD, of Sloan-Kettering Institute.

“Fra-1 is more likely to be causal than others because Fra-1 is going to be activating a whole lot of genes,” Dr. Holland said.

More study is needed before its exact role in cancer formation and growth can be determined, he added, but Fra-1's potential to be a strong therapeutic target makes that study all the more important.

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Teen Smoking Rates Leveling Off

After dropping for the past eight years, teen smoking rates appear to be leveling off, troubling many public health experts, according to a news release from Ohio State University Medical Center.

More than one million teenagers are becoming smokers each year, while the number of teens deciding to quit is decreasing. The trend may partly be due to the likelihood that antismoking campaigns have already prompted the most motivated smokers to quit, leaving behind the smokers who are most strongly addicted, noted Karen Ahijevych, PhD, RN, a smoking-cessation expert at Ohio State University Comprehensive Cancer Center.

“That seems to be the case with adults, but there have been so few studies about what's happening with kids that we're really not sure that's what's going on.” There is also a worry that financial support for antismoking campaigns is scarce. Many states have used millions of dollars from their Master Tobacco Settlement Agreements to offset budget deficits, and money from other sources for antismoking campaigns is also limited.

Dr. Ahijevych also emphasized the danger of tobacco use in teenagers: “People downplay the fact that kids can become addicted just like adults. We already know they need as much help quitting as adults do,” she said.

No one has figured out a single best way to help teenagers quit, but the solution may be a combination of family and school-based interventions, she said. “The best programs help individuals find out what's best for them. And usually that means a combination of tactics combined with a lot of support.”

© 2005 Lippincott Williams & Wilkins, Inc.
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