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Potential Brain Cancer Drug for Children May Damage Bones
Date:3/10/2008

od development.

The drug used by Curran's group acts on the hedgehog (Hh) pathway, which is known to play multiple roles during the development of mammals. Mutations of genes along that pathway lead to different cancers, including medulloblastoma, the most common cancerous brain tumor in children. Because conventional treatment with surgery, radiation and chemotherapy causes serious long-term side effects such as ataxia (a movement disorder) and cognitive impairments, the researchers sought novel, less toxic treatments for medulloblastoma.

In 2001, using genetic engineering, Curran bred mice to develop medulloblastoma. He then treated those mice with HhAntag, which had previously been developed by a biotech company for treating skin cancer in adults. In 2004, while at St. Jude's Children's Research Hospital, Curran reported highly promising results from the mouse studies. At high doses, the drug caused the tumors to shrink and in some cases, disappear entirely. The treated mice also survived much longer than untreated mice, with no serious side effects.

The drug seemed to be an unusually strong candidate for trials in children with the type of medulloblastoma having gene mutations on the Hh pathway--about a third of cases.

However, when Curran's group tested the agent on young mice (10 to 14 days old, in contrast to the adult mice tested previously), they found an unpleasant surprise: serious impairments to developing bones. The mice were smaller, with lower weight and shorter bones than untreated mice, and the effects were not reversible. Even four doses of the drug permanently stunted their growth. "We already knew that the same biological pathway involved in the growth of tumors was also involved in bone development," said Curran, "but we did not expect temporary inhibition to cause an irreversible change in bone growth."

While the current studies were disappointing, said Curran, they do not totally rule out a future r
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SOURCE The Children's Hospital of Philadelphia
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