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Protein may be key to new treatment in a childhood cancer
Date:2/7/2011

ma cells to die. Among those kinases, cell checkpoint kinase 1 (CHK1) had the strongest effect. "This screen was an unbiased study," said Cole. "We did not know beforehand which kinase would have the most potent effect. In fact, we would not have suspected CHK1, which was thought to be a tumor suppressor. It actually has the opposite effect in neuroblastoma. Its signals appear to drive neuroblastoma growth, likely by allowing them to tolerate stress to DNA caused by the MYC and MCYN oncogenes, which are active in neuroblastoma. Blocking CHK1 activity by RNA interference or by small-molecule inhibitors kills neuroblastoma cells."

When cancer cells are treated with chemotherapy, they can repair themselves though CHK1 signaling, making the chemotherapy less effective. Normal cells have redundant repair pathways and are not affected by CHK1 inhibition. Therefore CHK1 inhibitors are already being tested in adult clinical trials, in combination with chemotherapy, as a possible treatment for lung cancer, pancreatic cancer and other solid tumors. The current study suggests that neuroblastoma cells are particularly sensitive to CHK1 inhibition, without being combined with other agents.

CHK1 is not the first kinase with an important role in neuroblastoma. Some of the collaborators in this study from The Children's Hospital of Philadelphia previously discovered that the anaplastic lymphoma kinase gene (ALK), which carries the code for the ALK kinase, gives rise to some high-risk forms of neuroblastoma. Children's Hospital is currently testing ALK inhibitors in pediatric clinical trials of neuroblastoma, under the sponsorship of the Children's Oncology Group, a cooperative multicenter research organization.

"While it is compelling that there is single-agent activity in neuroblastoma," said Cole. "we anticipate that CHK1 inhibitors combined with chemotherapy will be significantly more potent." Cole expects pediatric oncologists to begin testing CHK1 i
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Contact: John Ascenzi
Ascenzi@email.chop.edu
267-426-6055
Children's Hospital of Philadelphia
Source:Eurekalert

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