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New Drug for Brain Cancer Too Dangerous for Pediatric Patients
Date:3/10/2008

Study found it caused permanent bone damage and stunted growth

MONDAY, March 10 (HealthDay News) -- A cutting-edge drug for brain cancers may place pediatric patients at risk for bone damage and stunted growth, an animal study suggests.

The new red flag concerns a signal transduction inhibitor (STI) medication known as "HhAntag", a drug developed to treat medulloblastoma brain tumors by short-circuiting tumor growth on the molecular level. The fear is that a therapy proven safe and highly successful among adults may pose a unique set of risks to young patients.

"Within just two days of treatment with HhAntag, we found a permanent shortening of bones and an alteration of joint structure among young mice," noted study co-author Tom Curran, deputy scientific director of the Stokes Research Institute at the Children's Hospital of Philadelphia.

"It's a little scary," he added. "Of course, the drug works well for about one-third of brain cancers. However, this is the first time it's really been tested in young animals. And the pathways that are targeted by this treatment are very active and important in developing children. So, we have a serious problem."

Curran and his team are publishing their findings in the March issue of Cancer Cell.

The authors noted that medulloblastoma is the most common pediatric central nervous system cancer. Although traditional non-STI treatments -- such as surgery, radiation and chemotherapy -- offer a five-year survival rate in almost four out of five children, such therapies often provoke severe side effects such as movement disorders and cognitive impairments. Those treatments are also far less effective among children under the age of 3 or among those whose disease has spread.

To date, HhAntag has achieved non-toxic results among adults -- targeting the so-called "hedgehog" pathway and shutting down a signaling mechanism critical to cancer cell proliferation. However, that same pathway regulates bone development.

Concerned that the drug might throw the baby out with the bathwater among younger patients, the researchers focused on mice between 10 and 14 days old, all genetically engineered to have cancer.

Several doses of HhAntag were tested over two-week treatment periods. The highest dose -- 100 mg/kg offered twice daily -- was found to be an ideal recipe for killing cancer.

However, X-rays revealed that after just two days, the therapy provoked widespread skeletal, cartilage and joint abnormalities, as well as impaired growth and weight loss. Even after cessation of treatment, the damage was irreversible.

Curran believes that the harsh STI consequences observed in young mice would be similarly manifested in children -- though to what degree remains unclear.

"So, for children we could potentially try to figure out how to deliver these drugs to the brain tumor and not the bones," he said. "But that will require a lot more research, which is unlikely to be performed by the pharmaceutical companies who wouldn't benefit financially, because the potential patient pool amounts to just a few hundred children per year for this kind of cancer."

"Without this research, we think the drug will only be useful for a subset of young patients," Curran noted. "Children with recurrent brain tumors, for example. Because, unfortunately, children who have relapsed don't live very long, and the side effects become irrelevant."

Dr. John S. Yu, co-director of the Comprehensive Brain Tumor Program at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute in Los Angeles -- shared Curran's concern.

"This study brings up a cautionary note for the long-term well-being of the young cancer patient," he said. "It certainly has significant repercussions for children with medullablastoma and other tumors that may be treatable with an expectation for a long survival. But, of course, I agree that for those children with a very long short life expectancy of a year or less, this problem would have less of an impact. In those cases, the treatment would certainly be worth the risk."

More information

For additional information on STIs and other targeted cancer drug therapies, visit the Hughes Cancer Center.



SOURCES: Tom Curran, Ph.D., professor, department of pathology, University of Pennsylvania, and deputy scientific director, Stokes Research Institute, Children's Hospital of Philadelphia; John S. Yu, M.D., director, surgical neuro-oncology, and co-director, Comprehensive Brain Tumor Program, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles; March 2008, Cancer Cell


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