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NEW RESEARCH ON BRAIN TUMORS Diabetes Drug Shows Promise for Preventing Brain Injury from Radiation Therapy
WINSTON-SALEM, N.C. – Researchers at Wake Forest University School of Medicine are the first to report that in animal studies, a common diabetes drug prevents the memory and learning problems that cancer patients often experience after whole-brain radiation treatments.
“These findings offer the promise of improving the quality of life of these patients,” said Mike Robbins, Ph.D., senior researcher. “The drug is already prescribed for diabetes and we know the doses that patients can safely take.”
Whole-brain radiation is widely used to treat recurrent brain tumors as well as to prevent breast cancer, lung cancer and malignant melanoma from spreading to the brain. About 200,000 people receive the treatment annually, and beginning about a year later, up to one-half develop progressive cognitive impairments that can affect memory, language and abstract reasoning.
In the current issue of the International Journal of Radiation Oncology - Biology –Physics, Robbins and colleagues report that rats receiving the diabetes drug piolitazone (sold under the trade name Actos®) before, during and after radiation treatments did not experience cognitive impairment.
The scientists compared whether treatment with Actos for four weeks or for 54 weeks after radiation would be more effective, and found there was not a significant difference.
The study involved young adult rats that received either radiation treatment equal to levels received by humans or a “sham” treatment involving no radiation. Animals in both groups received either a normal diet or a diet containing the diabetes drug.
Cognitive function was assessed a year after the completion of radiation therapy using an object recognition test. Rats receiving radiation exhibited a significant decrease in cognitive function, unless they received the diabetes drug for either four or 54 weeks after radiation.
“This could be easily applied to patients,” said Robbins, a professor of radiation biology. “We know the drugs don’t promote tumor growth, and in some cases may inhibit it.”
Currently, there are no known treatments to prevent cognitive impairments, and Robbins said the aging of the American population makes it imperative to solve the problem.
“Cancer is a disease of old age, so the number of people getting whole-brain radiation will increase,” he said.
In essence, radiation causes the cognitive problems because it speeds up the brain’s aging process. Recent research suggests that a cause may be chronic inflammation or oxidative stress. Oxidative stress occurs when cells cannot remove free radicals, or structurally unstable cells that can damage healthy cells.
The study by Robbins and colleagues was based on evidence that the diabetes drug pioglitazone prevents inflammation. The drug activates a specific type of peroxisome proliferator-activated receptors (PPARs) that control fat and glucose metabolism, and may be involved in inflammation.
Robbins said because the drug shows promise for preventing cognitive impairment, it may allow doctors to give higher doses of radiation. Currently, while higher doses of radiation have been associated with longer survival, dose is limited because of potential damage to surrounding healthy tissue.
ARTICLE FROM ST.JUDE'S Brain tumor researchers find their "niche"
Memphis, Tennessee, January 16, 2007
Brain tumors appear to arise from cancer stem cells (CSCs) that live within microscopic protective “niches” formed by blood vessels in the brain; and disrupting these niches is a promising strategy for eliminating the tumors and preventing them from re-growing, according to results of a study by investigators at St. Jude Children's Research Hospital. CSCs are cells that continually multiply, acting as the source of tumors.
“The finding that brain CSCs exist in protective vascular (blood vessel) niches helps explain the origin of brain tumors and suggests a new strategy for eliminating them,” said Richard Gilbertson, M.D., Ph.D., co-director of the Neurobiology and Brain Tumor Program at St. Jude. Gilbertson is senior author of a report on this work that appears in the January issue of Cancer Cell.
“Our data indicate that brain CSCs are nurtured by these vascular niches and that disrupting them blocks tumor growth by removing CSCs from tumors,” he said. “These niches might also protect CSCs from chemotherapy drugs and irradiation therapy. So our findings could explain why aggressive tumors rapidly produce new blood vessels and why brain tumors reappear following treatment.”
The St. Jude team first determined that CSCs are located in vascular niches by identifying cells carrying a protein called Nestin that marks stem cells (Nestin+ cells) in four types of brain cancer removed from patients: medulloblastoma, ependymoma, oligodendroglioma and glioblastoma. They found that tumors with the densest system of tiny blood vessels contained the greatest number of Nestin+ cells, and that Nestin+ cells are located next to blood vessels in brain tumors.
The investigators then examined thin sections of brain tumors and found that more than one-third of the Nestin+ cells next to blood vessels in the vascular niches had a mutation known to be linked to cancer, which suggested they were CSCs, Gilbertson said. About 30 percent of these cells were multiplying abnormally and rapidly, as expected for cancer cells.
The team showed in mouse models that CSCs from brain tumors have a more natural tendency to associate closely with blood vessels than do non-CSC tumor cells. The researchers also demonstrated in test tube experiments that CSCs bind closely to cells isolated from human blood vessels. Further, the investigators found that human blood vessel cells release molecules that trigger brain CSCs to keep their identity as stem cells and continue to multiply rapidly.
“This is strong evidence that the cells making up the vascular niche send signals to CSCs in the brain, causing them to grow and multiply,” Gilbertson said.
Gilbertson’s team also studied the interaction of blood vessel cells with CSCs using mouse models of brain cancer. Mixing brain CSCs with human blood vessel cells dramatically increased the formation and growth of tumors. Brain CSCs inserted into the brain without human blood vessel cells produced tumors slowly, reaching a maximum size after seven weeks. In contrast, tumors formed by mixtures of brain CSCs and blood vessel cells grew much more rapidly, reaching a maximum growth after only four weeks. The blood vessel cells did not increase tumor growth by forming new vessels, but by associating with CSCs and stimulating these directly to produce tumors.
Finally, the investigators showed that increasing the numbers of blood vessels in mouse models of brain tumors markedly increased the numbers of CSCs in tumors. The scientists also showed that drugs that deplete blood vessels from tumors inhibit tumor growth by reducing the number of CSCs. For example, the team depleted blood vessels in tumors with Avastin® (bevacizumab), an anti-angiogenic drug that blocks a protein called VEGF. Anti-angiogenic drugs block the formation of new blood vessels.
“This strongly suggests that disrupting the blood vessels in brain tumors might block tumor growth by disrupting brain CSC niches,” Gilbertson said. “This is important since the mechanism by which anti-angiogenic drugs, like Avastin, block tumor growth is largely unknown. Our data suggest a previously unrecognized way that anti-angiogenic agents inhibit tumor growth.”
The St. Jude investigators have now translated these findings into a clinical trial to determine the effectiveness of Avastin and another drug, Traceva® (erlotinib), in eliminating tumors and preventing their recurrence in children with brain cancers.
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