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Reversing drug resistance in leukemia

Children with acute lymphoblastic leukemia (ALL), a relatively common childhood cancer, usually respond very well to steroids—in particular, glucocorticoids like prednisone. However, some children's cancers are resistant to glucocorticoids, making them apt to suffer relapses. Children's pediatric oncologist Scott Armstrong, MD, PhD, has now found an existing drug that may turn this resistance around.

Armstrong tapped the Human Connectivity Map, a freely available online database unveiled by collaborating researchers at Harvard and MIT in 2006. The map, which Armstrong helped validate, has been described as a Google-type approach that allows researchers to systematically compare the gene expression "signatures," or patterns of gene activity, of diseased cells (such as tumor cells) with the signatures of cells treated with different drugs. "It's kind of like matching up barcodes," Armstrong says.

When Armstrong ran cell samples from patients with ALL who were either resistant or sensitive to glucocorticoids through the map's database, the genetic signatures predicted that rapamycin, a drug used to prevent post-transplant tissue rejection, would also be a good candidate for reversing glucocorticoid resistance. And indeed, in tissue culture, rapamycin made leukemia cells more sensitive to glucocorticoid therapy.

Earlier this year, Armstrong and colleague Lewis Silverman, MD, opened a clinical trial to assess whether rapamycin has the same effects in patients with relapsed ALL—the first human study of a drug to come out of the Connectivity Map project. "Once we've determined the right dose and that rapamycin has the biological effect we want in patients, we'll move to a bigger trial to see if combining rapamycin with steroids affects treatment outcome," Armstrong says.