December 29, 2010 — The cancer stem cell hypothesis has been given a boost by new clinical data from a study in patients with acute myeloid leukemia (AML).
The new finding is reported in the December 22/29 issue of the Journal of the American Medical Association by researchers from Stanford University, who say the clinical implications are "huge."
According to the cancer stem cell theory, cancer is caused and maintained by a small group of hardy, self-renewing cells, and only eradication of this cell population will lead to a cure.
The strongest support for this theory thus far has come from transplantation assays in immunodeficient mice, "which indicate that human AML is driven by self-renewing leukemic stem cells," the researchers comment in their paper.
Now, however, they report new clinical data that support the hypothesis.
Andrew Gentles, PhD, and colleagues from Stanford University School of Medicine in California, studied the medical records of 1047 patients with AML. They found that patients with AML who had higher activity of certain genes associated with leukemic stem cells had worse outcomes than the other patients.
"The stronger the leukemic stem cell signal, the worse the patients did," Dr. Gentles commented in a statement. "Their lives were shorter, they relapsed sooner, and they were less able to respond to therapy," he added.
For example, in a group of patients from Germany, those with a higher score for leukemic stem cells had a 78% chance of dying within 3 years compared with 57% for patients with lower scores.
Patients with higher scores for leukemic stem cells also had a worse response to induction therapy, and fewer of them went into remission.
The researchers found that gene expression pattern for the stem cells was similar to that found on normal blood cells, which suggests that these stem cells can self-renew but divide infrequently. The authors speculate that in this way these cells are able to escape conventional therapy, which targets rapidly dividing cells.
"It's almost as if these cells are lurking in the background, waiting to pounce after chemotherapy has wiped out most of the other cells," commented senior author Ash Alizadeh, MD, PhD.
"The clinical implications of this concept are huge," Dr. Alizadeh commented in a statement. "If we're not able to design therapies to target this self-renewing population of chemotherapy-resistant cells, the patients will continue to have a tendency to relapse."
"We've made very little progress in the treatment of AML over the past 40 years," Dr. Alizadeh continued. "We're still using the same drugs and therapies we've always used, even though about 70% of patients with AML die within 5 years of diagnosis."
The team's finding that prognosis is worse in patients with AML who have a higher scorer for leukemic stem cells comes from a retrospective study, and the patients involved were treated at several different centers (in the Netherlands, Germany, and Japan, as well as in the United States).
Validation in a prospective study with uniform treatment is now required, but if the finding is prospectively validated, it could become useful clinically; for example, for identifying patients with a worse prognosis, and perhaps in the future for deciding which therapies to use and which to avoid.
Validation may "help us to determine whether individual patients should participate in clinical trials or if their initial treatment should be more aggressive than standard approaches," commented coauthor Ravindra Majeti, MD, PhD.
"This finding adds to our clinical confidence that the cancer stem cells hypothesis is important to human disease," Dr. Majeti noted.
"Ultimately, this model has major implications for cancer therapy," the researchers conclude. "Most notably, that in order to achieve cure, the cancer stem cells must be eliminated."
"To accomplish this in AML, novel therapies targeting leukemic stem cells must be developed," they add.
The study was supported by grants from the National Institutes of Health, the Burroughs Wellcome Fund, and the Leukemia and Lymphoma Society. Dr. Gentles, Dr. Majeti, and Dr. Alizadeh report that they have submitted a patent application for use of the leukemia stem cell gene expression score as a diagnostic assay.
JAMA. 2010;304:2706-2715. Abstract
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