Some know Gleevec, or imatinib, as a wonder drug that has dramatically improved the treatment of chronic myelogenous leukeumia (CML); yet patients can still relapse despite therapy because the disease lurks in dormant stem cells.
Now City of Hope’s Bin Zhang, Ph.D., and colleagues may have found how to destroy this hidden reservoir of treatment-resistant CML stem cells — potentially eradicating the disease. The scientists presented their work at the 51st annual American Society of Hematology (ASH) meeting in New Orleans in December 2009. Data from more than 30 City of Hope studies were presented during the four-day event.
 Investigators Ravi Bhatia, left, and Bin Zhang aim to eradicate leukemia stem cells. (Photo by Thomas Brown) |
Zhang, a clinical research fellow in the Division of Stem Cell and Leukemia Research, and her fellow researchers at City of Hope and other institutions believe they are the first to demonstrate that drugs called histone deacetylase (HDAC) inhibitors, in combination with Gleevec, can target stem cells that otherwise resist therapy.
Ravi Bhatia, M.D., director of the Division of Stem Cell and Leukemia Research, was senior author on the study. He explained that while Gleevec is a successful therapy, it is not perfect.
“Gleevec makes most of the diseased cells go away, but there is a very small population of diseased cells that escape elimination by Gleevec,” explained Bhatia. “Gleevec is good at suppressing the proliferation of cells, but not those that lie dormant and survive. If Gleevec were stopped, cells could start proliferating again and regenerate.”
However, when physicians combine HDAC inhibitors with Gleevec, the combination is “very effective in killing CML stem cells — including the dormant ones,” said Bhatia.
Their research has led to a clinical trial of the investigational drug LBH589, or panobinostat, for CML, which began late last year and is still recruiting patients. During ASH, researchers also presented an abstract about their initial work on the clinical trial.
“If we are successful, the ultimate aim would be that we could give this drug in combination with Gleevec, and these patients would go from having remission with residual cells to being cured of leukemia,” said Bhatia.
“That’s what we’re trying to do — take the patients from being in remission to being cured,” he added.
Zhang noted that initial results “support ongoing clinical trials of these inhibitors combined with imatinib to eliminate residual leukemia stem cells in imatinib-treated CML patients.”
Potentially, this combination of drugs also may be successfully applied to other leukemias and cancers, including myelodsyplastic syndrome, acute myeloid leukemia and perhaps breast and colon cancers, Bhatia said — diseases in which recurrence is thought to come from a reservoir of cancerous stem cells.
Other City of Hope staff members contributing to the study included Adam Campbell Strauss, M.S., Su Chu, M.D., Yin Wei Ho, M.S., and David S. Snyder, M.D.
Researchers also included Claudia Huettner, Ph.D., from the Dana-Farber Cancer Institute, Lenny Shultz, Ph.D., from The Jackson Laboratory in Bar Harbor, Maine, and Tessa L. Holyoake, Ph.D. from the University of Glasgow, Scotland.
