Gleevec rocked the cancer community when it appeared on the scene in the late 1990s. Able to provide long-term, stable remission for chronic myeloid leukemia (CML) patients, it’s nothing short of a wonder pill. It does have a major shortcoming, though — for most patients, it doesn’t actually cure the disease.
 Ravi Bhatia targets leukemia stem cells in a new clinical study. (Photo by Markie Ramirez) |
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 trial 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. But Bhatia’s previous studies showed the drug doesn’t eliminate all the cells that give rise to the disease. In fact, patients must keep taking the drug to keep their cancer under control.
“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 recurrence.”
Stem cells are the “parent” cells that develop into other cell types found in bodily organs.
Leukemia stem cells lurk in the patient’s marrow waiting to develop into mature, disease-causing cancer cells. Because they’re not fully developed yet, 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 together 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 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.”