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    The big picture

    How can we design more effective chemotherapy for childhood leukemia? St. Jude researchers look at the big picture—and find intriguing answers.

    Genes. There are thousands of them in the human genome. Some determine eye color. Some determine height. Some increase the likelihood of cancer. Scientists have long understood that the cancer cell’s genes play a major role in the outcome of cancer therapy. But St. Jude Children’s Research Hospital scientists recently illustrated that other genetic factors can also contribute significantly to the outcome of therapy.

    St. Jude researchers discovered in children with acute lymphoblastic leukemia (ALL) a host of inherited genetic variations that may help clinicians design more effective chemotherapy. The findings are crucial because individual patients can respond differently to the same drug.

    “This study differs from most previous investigations of gene variations linked to chemotherapy outcome because those studies focused only on the genes of the leukemic cells themselves,” says Mary Relling, PharmD, St. Jude Pharmaceutical Sciences chair. “We focused on variation that is inherited and affects all cells in the body, not just the leukemic cells.”


    Foresight rewarded

    For more than 20 years, St. Jude has been saving samples of DNA from patients in anticipation of the day when technology would allow researchers to take a broad, genome-wide approach toward cancer treatment. Not that long ago, researchers could only study one gene at a time. But times have changed.

    “Instead of looking at one gene,” Relling says, “we can do a genome-wide interrogation of all 20,000 genes in the human genome.”

    Relling and her colleagues are especially interested in single nucleotide polymorphisms, or SNPs (pronounced snips). SNPs are DNA sequence variations that occur when a single DNA building block called a nucleotide in the genome sequence is altered. SNPs can predispose children to disease or influence their response to drugs. Using a high-tech tool known as a SNP chip, St. Jude scientists can now screen a million SNPs per patient.

    In an effort to determine how inherited genetic variation affects children with ALL, St. Jude collaborated with the Children’s Oncology Group (COG), the national network of hospitals treating childhood cancers. Relling and her colleagues obtained DNA from 487 children with newly diagnosed ALL who were treated on either St. Jude or COG clinical trials. The scientists studied the DNA making up genes inherited from the parents, in contrast to the DNA that originated from the patients’ tumor cells.

    Researchers looked for SNPs that might predict why some children have a good response to the first few weeks of chemotherapy and others do not. Early response was measured by assessments of minimal residual disease (MRD), the small number of leukemic cells that survive after remission induction therapy. This measurement helps clinicians identify patients whose disease is highly responsive to chemotherapy and therefore might be cured with milder and less toxic treatment, and which are more resistant and thus need more aggressive chemotherapy.

    Then researchers searched for inherited SNPs. “Working with our statisticians, we found 102 SNPs out of 600,000 that were associated with eradication of MRD at the end of the induction phase in these children,” Relling says. “Of those 102, about 60 were also associated with related characteristics, such as relapse risk, drug exposure and very early response.”

    The scientists studied the relationship between the SNPs and three measures of total body exposure to the medicines that St. Jude uses to treat childhood leukemia. If a patient clears the drugs quickly, the blood levels of the anti-leukemic drugs in these children will be low. A high percentage of the 102 SNPs associated with lower levels of MRD were also associated with slow drug clearance or higher levels of anti-leukemic drugs in the ALL cells.

    “That makes a lot of intuitive sense,” Relling says. “Part of the way that inherited variation affects anti-leukemic response is by affecting the efficiency of gene products that metabolize and excrete medicines.”


    Surprise candidate

    The researchers discovered five SNPs that are located in and around a gene called IL15, which codes for a protein that stimulates multiplication of leukemic cells. Other research has shown that this gene is related to drug responsiveness of blood cells.

    “It makes sense that IL15 could be related to whether the child’s leukemia cells respond well to therapy or not, but the findings are interesting because it would not have been anybody’s top candidate gene,” Relling says. “We have had our list of genes that we have been working on for the last 20 years, but those genes do not tend to be the ones that are the hits we get from these genome-wide surveys.”

    “It could be that IL15will be a good target for new anticancer drugs, or it will help us assign patients into risk groups, which are used to modify therapy based on those risks,” Relling says.

    Some of the 102 SNPs probably work by directly affecting the responsiveness of the ALL cells. Just because it is inherited, that does not mean that genetic variation disappears in the leukemia cells that arise in the body. The leukemia cells that arise in a child are influenced by the genetic variants the patient inherited from the parents, as well as by genetic variants the patient acquired in the bone marrow cells that made the leukemia cell arise in the first place.

    Relling, Yang and their colleagues published their findings in the Journal of the American Medical Associationearlier this year. Based on the success of that project, St. Jude is collaborating with COG on several other genome-wide studies.

    “Our results show the importance of surveying variations in the entire human genome in normal cells from patients, since many such variations can determine the effectiveness of chemotherapy,” says Jun Yang, PhD, a postdoctoral fellow in St. Jude Pharmaceutical Sciences. “In the future, such information might help clinicians use drugs more effectively to overcome the patient’s own genetic variation and reduce the chance of treatment failure.”

    Reprinted from Promise Spring 2009

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