Able to provide long-term, stable remission for chronic myeloid leukemia (CML)
patients, the drug Gleevec is nothing short of a wonder pill. It does have a major
shortcoming, however — for most patients, it does not actually cure the disease.
Fortunately, Ravi Bhatia, M.D., director of the Department of Hematopoietic Stem
Cell and Leukemia Research, may have found a way to finish the job Gleevec starts.
He recently began a clinical study to test his method.
Gleevec works by blocking a protein called BCR-ABL, which causes normal white blood cells to become cancerous, resulting in CML. However, in previous studies, Bhatia found the drug does not eliminate all of the cells that give rise to the disease. In fact, patients must continue to take the drug to keep their disease under control.
|Ravi Bhatia targets leukemia stem cells in a new clinical study. (Photo by Markie Ramirez)|
“CML is well-controlled while the patient takes Gleevec, but if we stop giving it, the
disease returns,” explained Bhatia. “Leukemia stem cells are the source of this
Leukemia stem cells lurk in the patient’s marrow waiting to develop into mature,
disease-causing cancer cells. Because they are not fully developed, Gleevec has no effect on them. Even more ominous, while the leukemia stem cells lie in wait, some of them can become resistant to Gleevec. When they grow into adult cells, the patient develops leukemia again.
By giving patients Gleevec in combination with another drug, labeled LBH589, Bhatia believes he may have a one-two punch that will eliminate CML completely.
LBH589 belongs to a class of drugs called histone deacetylase inhibitors. These drugs, more commonly called HDAC inhibitors, cause cancer stem cells to self destruct in a process known as apoptosis.
The body usually uses apoptosis to get rid of worn-out or faulty cells. But in cancer, that process can get turned off, allowing dangerous faulty cells — cancerous ones — to survive. HDAC inhibitors may restore the helpful process and help other drugs better do their cancer cell-killing work.
“We showed in preclinical studies that the combination of an HDAC inhibitor and Gleevec was very effective in eliminating both mature CML cells and leukemia stem cells,” said Bhatia.
Bhatia is collaborating with Rama Natarajan, Ph.D., professor in the Department of Diabetes, Endocrinology & Metabolism, to determine how the HDAC inhibitor prompts apoptosis in the cells. The pair plans to search for genes linked to
apoptosis that are affected by the drug.
In the current clinical study, Bhatia hopes to see the drug combination work as effectively in patients as it has in the laboratory. “Gleevec currently is the first-line treatment for CML, but patients must remain on the drug to control the disease,” he said. “We would like to find a way to free them of that need and eliminate any
possibility of relapse.”
However, the new treatment is not without the possibility of side effects, he cautions.
“The HDAC inhibitor does affect normal cells,” he explained. “This is a phase I study, so our primary goal is to determine the maximum safe dose we can give.”
Study coordinators enrolled the trial’s first patient in mid-June. Bhatia is collaborating with researchers at Fred Hutchinson Cancer Research Center on the study.