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http://www.scienceda...31021061411.htm
Source: Stanford University Medical Center
Date: 2003-10-21


Drug May Treat Previously Incurable Brain Cancer, Say Stanford Researchers

STANFORD, Calif. - An old drug may have found a new role treating an incurable form of brain cancer called glioblastoma, according to preliminary research at Stanford University School of Medicine. The drug, called arsenic trioxide, increases the effectiveness of radiation therapy in mice with the disease. The researchers will present their work Oct. 22 at the American Society for Therapeutic Radiology and Oncology.

"Many brain cancers are incurable," said Susan Knox, MD, PhD, associate professor of radiation oncology, who led the study. "The use of arsenic trioxide with radiation may be one way to make the treatment more effective."

Arsenic trioxide has been approved by the U.S. Food and Drug Administration for use in treating a rare form of leukemia. It works in part by releasing damaging molecules called reactive oxygen species, or ROS, that destroy cancer cells. Shoucheng Ning, MD, PhD, a research associate working with Knox, thought the drug would release even higher levels of ROS when coupled with radiation therapy.

The team tested this idea in both the lab dish and in mice. In both cases, exposing glioblastoma cells to radiation within two hours of receiving a dose of arsenic trioxide amplified the effects of radiation treatment on its own.

The mice in this study had tumors formed by injecting human glioblastoma cells under the skin. In these mice, arsenic trioxide alone did not slow the tumor growth, and radiation alone delayed the tumor's growth for only 45 days. The combined treatment eliminated the tumor in four out of five mice and shrunk the tumor by 90 percent in the fifth mouse. The tumors had not begun growing again when the trial ended three months later.

Ning said that the arsenic trioxide dose the mice received is low enough that it would not be toxic in humans. "The concentration we used is already known to be achievable and is well tolerated in humans," he said.

"Based on these results we think the data are compelling enough to move forward with human trials," Knox said. She hopes to start preliminary human trials in conjunction with Iris Gibbs, MD, assistant professor of radiation oncology, by next year. The initial trials will be in recurrent glioblastoma and pediatric brain stem glioma, though Knox hopes to test the therapy in other cancers in the future.

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http://www.scienceda...31205051621.htm
Source: Duke University Medical Center
Date: 2003-12-05

Researchers Use Crippled Poliovirus To Attack Brain Cancer
DURHAM, N.C. -- In a daring yet successful experiment to cure deadly brain tumors, researchers have combined the cancer-killing properties of poliovirus together with a harmless genetic coding element from the common cold.

Reengineered Poliovirus Proves Effective As Vector For Prompting Key Immune Response In A Study With Mice

Antiviral Drug Works By Causing "Genetic Meltdown"

The resulting modified virus created a remarkably strong anti-cancer agent that rapidly killed cancer cells in laboratory cell cultures and in animals -- and without causing polio, said Matthias Gromeier, M.D., assistant professor of molecular genetics and microbiology at the Duke Comprehensive Cancer Center. Testing of the new viral agent in humans should begin within two years, he said.

In the study, the modified poliovirus rapidly killed cancer cells derived from primary brain tumors as well as cells derived from breast and colon cancer metastases -- all within a matter of four to six hours. In fact, polio is known to be one of the quickest killers of infected host cells, producing approximately a thousand additional infectious viral units per infected cell, he said.

"We made a drug out of a virus by engineering its destructive abilities from a foe into a friend," said Gromeier. His most recent results -- a collaborative effort with Darrell Bigner, M.D., Henry Friedman, M.D., Allan Friedman, M.D., and John Sampson, M.D., of the Brain Tumor Center at Duke -- will be published in the Dec. 9, 2003, issue of the Proceedings of the National Academy of Sciences, which is currently available online.

The key to Gromeier's success has been disabling the poliovirus' ability to kill normal brain cells while retaining its ability to kill cancer cells in the brain. To do so, Gromeier's team swapped a critical genetic element from the common cold "rhinovirus" with the corresponding genetic element from the poliovirus. The genetic element, called an "IRES" (internal ribosomal entry site), enables a virus to express its own genetic information inside the host cell it has invaded, said Gromeier.

Gromeier selected the IRES from a rhinovirus because it does not typically infect the human brain. Normal brain cells lack the appropriate environment required for the rhinovirus IRES to begin translating the poliovirus's genetic information, his study demonstrated.

Cancer cells, however, regulate gene expression very differently than normal cells do. They grow faster, lack growth inhibitors and generally provide a supportive environment that is highly susceptible to viruses of all sorts, making viruses an excellent invader to disrupt cancer's growth. "In cancer cells, the IRES from rhinovirus acts as the trigger that activates gene expression, but the genes being expressed -- the silver bullets in the gun, so to speak -- are all from the poliovirus," said Gromeier. "The polio proteins kill the cancer cells quickly and efficiently."

In fact, polio is the perfect virus to attack brain cancer cells because it has a natural affinity for invading the brain, said Gromeier. Polio infects brain cells by binding to a receptor or "docking site" called CD155 on the outside of motor neurons. Gromeier showed that brain tumors over-produce this CD155 receptor, making the cancer cells particularly vulnerable to infection with poliovirus. The modified poliovirus still enters normal motor neurons because it shares the same CD155 receptor as brain tumor cells, but it can no longer grow in normal cells.

"We have a virus that naturally targets brain cells, but we have replaced the genetic coding element that makes the virus so dangerous," said Gromeier. "The virus has lost its ability to grow in normal neurons."

Tests in mice and in non-human primates have confirmed that the modified poliovirus does, indeed, kill brain tumor cells but does not affect normal motor neurons. Moreover, viruses don't carry the toxic side effects of chemotherapy and radiation, and viruses can be introduced directly into the tumor.

"The brain is a very common site of cancer metastasis, but cancer in the brain is extremely difficult to treat," said Gromeier. "Cancer cells are often interspersed throughout normal brain tissue, and most chemotherapy does not cross the blood-brain barrier, so getting the drug to the target site of treatment is a huge problem clinically."

To combat that problem, the modified poliovirus is directly injected into the brain tumor. Once there, the virus seeks out and destroys cancerous cells without detection by the body's immune system. The immune system would normally neutralize the poliovirus in vaccinated individuals because they have built up antibodies against polio. But the brain does not have immunity against polio because antibodies do not cross the blood-brain barrier. Hence, infusing the brain directly with modified polio is the most effective method of killing cancer cells.

But giving the modified poliovirus to humans -- even to terminal brain cancer patients -- requires rigorous testing to understand the mechanism behind its virulence in cancer cells and its impotence in normal brain cells.

So, Gromeier's team embarked on a mission to elucidate the molecular mechanism that causes the rhinovirus IRES to function in cancer cells but to malfunction in normal neurons.

After extensive testing, he discovered that the IRES from the rhinovirus communicates with the opposite end of the poliovirus genome. That distant region, called the 3-prime non-translated region, drives how the virus transmits its genetic instructions inside the host cell. Gromeier's data suggest that -- in cancer cells -- the rhinovirus IRES and the 3-prime communicate via a set of proteins, called co-factors, which ignite the IRES to begin functioning.

Normal motor neurons, however, may not provide the appropriate set of co-factors to stimulate rhinovirus IRES function, said Gromeier. Hence, the modified virus cannot grow in normal motor neurons.

"Cells differ in terms of how well-suited they are to a particular virus," said Gromeier. "Every cell type has unique cellular proteins that can either support or block viral function, and we believe differences in these proteins account for the modified virus' inability to infect normal brain cells."

The research was funded by the National Institutes of Health, the National Cancer Institute, The Burroughs Wellcome Fund, ABC2 Foundation, and the Brain Tumor Society.