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Releases Packard
Children's News
Children's Fund
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Genetic Signposts Point the Way to
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Still to be conquered, however, is acute myelogenous leukemia (AML)—a rare, fast-moving form of the disease. Children with AML face an uphill battle during treatment and significantly lower survival rates along the way.
Aggressive chemotherapy helps more than half of AML patients go into remission, and those who qualify for bone marrow transplants have a 70 percent chance of recovery. But the side effects of all the required treatments are severe, including a weakened immune system that leaves children vulnerable to other diseases and complications. Even those children who go into remission frequently face a recurrence of AML, which is more difficult to treat.
Pediatric oncologist Gary Dahl, MD, of Lucile Packard Children's Hospital and his collaborators at the School of Medicine's Cancer Center are determined to find better treatments for this deadly disease. They are focusing on genetic codes embedded deep in patients' cancer cells to tailor therapies to individual children, creating better chances for survival.
"Aggressive standard chemotherapy has pretty much reached its limit in AML, and we have to look elsewhere for new therapeutic strategies," Dahl explains.
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| 12-year-old Michael Linehan is fighting acute myelogenous leukemia. Packard oncologist Gary Dahl, MD, is able to finetune treatments for Michael and other patients by closely studying their genetic profiles. |
Using two techniques developed at Stanford -- microarray chip technology and genetic expression profiling -- Dahl is working with Norman Lacayo,MD, assistant professor of pediatric oncology, to conduct a genomewide analysis of bone marrow samples from 300 children who have been treated for AML.With help from biostatistics professor Robert Tibshirani, PhD, who is analyzing the vast amount of data, the team is sifting through the more than 30,000 genes in the leukemic cells of each patient, looking for over- or underexpressed genes, which may signal which treatment might work best for particular children.
Ultimately, Dahl plans to use the data to target specific treatments for groups of patients. For example, he already has found that children whose leukemic cells show mutations to a certain gene, known as FLT3, do not respond as well to conventional treatment as other patients and may require a more aggressive therapy. By examining their genetic profiles, doctors can offer these AML patients alternative treatments up front, before other therapies have failed.
This approach not only could create a fundamental shift in treating leukemia, but it also could shed light on how to use genetic signposts in curing other diseases. Instead of treating all patients with one standard therapy, physicians could use genetic markers as a guide to zero in first on the drug most likely to cure a patient.
Dahl already is putting his findings to work as part of a collaborative trial at Packard Children's under the aegis of St. Jude Children's Research Hospital in Memphis, Tenn. Children participating in the clinical trial were given individualized therapy tailored to their own genetic risk factors. While results are not in yet, Dahl says that similar trials using genetic markers to select leukemia treatments have shown successful results.
In addition to harnessing genetics to identify the best treatment possible, Dahl is working with other scientists to use information from inside leukemic cells to develop entirely new therapies for leukemia patients.
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| Pathway analysis reveals abnormalities in a cancerous cell's chromosomal structure. |
He has turned to a technique developed by Stanford geneticist, Garry Nolan, PhD, which allows scientists to see metabolic, molecular-level pathways inside cells, gaining a window into how leukemic cells operate.
"We are excited about this new approach because it may give us information as to why treatments fail for certain patients and which newly developed therapies should be used," Dahl says. Future drugs could manipulate cells' pathways, causing them to self-destruct or die more quickly when subjected to chemotherapy. Using a patient's genetic risk factors, doctors could anticipate a poor reaction to chemotherapy and prescribe a molecular pathway inhibitor as a first line of attack.
Dahl expresses hope that these novel genetic approaches will improve the outlook for his young patients. After years of increasing the odds -- only 3 percent of AML patients survived three decades ago -- the cure rate has reached a plateau recently at around 50 percent. But through genetic and cellular techniques, leukemia research at Packard may be turning a corner in finding the right therapies for each child.
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