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Neuroblastoma Stem Cells Targeted with Repurposed Drugs

Victorian, Brande

doi: 10.1097/01.COT.0000390352.18177.50


Researchers may have found a way to get treatment to cancer patients faster by testing existing drugs on the cancer stem cells of children with neuroblastoma, according to a study in the September issue of EMBO Molecular Medicine (2010;2:371-384).

In the study led by Kristen M. Smith, a postdoctoral fellow at the Hospital for Sick Children (SickKids) in Toronto, the researchers set out to identify the cells involved in the development of neuroblastoma by isolating cancer stem cells from bone marrow metastases in children, targeting the cells responsible for disease relapse.

Using between one and 10 cells from the children, the researchers were able to form neuroblastomas in mice. In contrast, historically, many thousands of cells have been needed to form these tumors, said principal investigator David R. Kaplan, MD, who is a Senior Scientist at SickKids and Professor in the Department of Molecular Genetics at the University of Toronto.



“If you can get one to 10 cells to form tumors in mice and you find a drug that can kill those cells, we might have a better chance of killing or getting rid of the cells responsible for relapse.”

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Old Method, New Approach

Beyond identifying the cells responsible for neuroblastoma, the researchers also wanted to find a way to move drugs more quickly from bench to bedside. To do so, rather than attempting to develop new drugs, they instead tried repurposing existing medications identified as being effective in neuroblastomas by small molecule screens.

“What's really novel is the cells that we use. They are cells directly from the patient that we think are responsible for relapse and we combined them with an approach that many of us are trying to use in cancer care, which is repurposing drugs,” Dr. Kaplan said.

Various drugs passed the initial screening, which also tested normal cells of children to make sure that they were left unaffected, but two medications in particular were found to be especially suited for treating neuroblastomas: DECA-14, a version of a drug that had been used in mouthwashes as an antibiotic; and rapamycin, which is used to prevent organ rejection and is also in clinical trials for some adult cancers.

“Rapamycin was very potent in killing the cells directly from the patients; it had no effect on their normal cells; and in mice, in a week or two, it completely got rid of human neuroblastoma cells that had been injected into them,” Dr. Kaplan said.

After a pilot study led by one of the coauthors, Sylvain Baruchel, MD, Senior Associate Scientist at SickKids, of five children treated with rapamycin and vinblastine showed promising results, two foundations provided funding for a Phase I clinical trial to be conducted on 25 children at five treatment sites in North America.

Because profiles have already been done on rapamycin's toxicity and appropriate dosage levels, the researchers were able to begin a clinical trial for this indication much faster than they would have been able to with a new drug, Dr. Kaplan noted.

“For us this is exciting, because this is an example where we hope a child can come to a hospital, we'll isolate their cancer stem cells, screen them with libraries of drugs, see which ones work, and then we can put the particular child on that drug.”

© 2010 Lippincott Williams & Wilkins, Inc.
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