Signaling blocker halts bone growth

Inhibiting a key signaling pathway causes permanent damage to bones in young mice, researchers report in this week's issue of linkurl:__Cancer Cell.__;http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWK-4S1BVT4-9&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=80258615088ab83976bfb4ac64c10eb7 The findings suggest that drugs targeting this pathway, under development for solid tumors, may have unexpected drawbacks if used in children. The finding "was a bit of a shock," said Tom Curran at the Children's Hospital of Pennsylvania and the principal investigator on the study. Curran had been looking at an inhibitor of the Hedgehog (Hh) pathway for its potential therapeutic effects on a childhood brain cancer, medulloblastoma (MB). Approximately a third of patients with MB, predominantly a childhood cancer, have mutations or involvement of Hh pathway genes, which made the antagonist a promising drug target. But while testing the efficacy of the compound in mice, researchers in Curran's lab noticed the treated mice were unusually small. When they x-rayed the mice, they found widespread defects in skeletal structure. The tips of the bone stopped growing in response to the drug, and the longer the drug was administered, the shorter the bones became. Although many drugs can damage bone integrity, the changes are usually reversed when the drug is removed from the system, said Curran. The effects of the Hh blocker on young mice, however, caused permanent damage, even at low doses. The study has important implications for using signal transduction inhibitors in pediatric patients, Curran told __The Scientist.__ Many signaling pathways such as those involving linkurl:Wnt;http://www.the-scientist.com/2008/3/1/34/1/ and Notch proteins are important in cancer, but also play a critical role in development. Anti-cancer drugs that inhibit these pathways need to be examined carefully before being applied in children, said Curran.

Signaling blocker halts bone growth

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