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05/02: Gene mutation lets leukemia fight drug that helps remission
BC Cancer Agency researchers discover that one chemotherapy alone may not work
Mutations in the cancer stem cells of patients with chronic myeloid leukemia (CML) may prevent an initially useful therapy from being effective after several years, according to new research at the BC Cancer Agency, an agency of the Provincial Health Services Authority.
Published today in the Journal of the National Cancer Institute, scientists at the BC Cancer Agency’s Terry Fox Laboratory have discovered that CML stem cells spontaneously develop resistance to Gleevec, an oral chemotherapy that helps reduce the symptoms of CML and allows patients to return to a normal life.
For most patients with chronic phase CML, Gleevec produces a remission; however, relapses are common and the usual finding is that the re-emerging leukemia has become resistant to the drug. The BC Cancer Agency researchers speculated that such relapses are due to an ongoing tendency of the leukemic stem cells to acquire mutations in the BCR-ABL gene even before the patient is exposed to Gleevec.
The BCR-ABL gene causes the leukemia and Gleevec works as a therapy because it specifically inactivates the BCR-ABL protein. When the gene mutates, the altered protein produced may still drive the leukemia but be resistant to drug inactivation.
This is exactly what lead researcher Dr. Xiaoyan Jiang found upon examining the leukemic stem cells from patients who had never received any Gleevec. The leukemic stem cells already contained many mutations. “Because Gleevec is unable to kill the mutant stem cells, they begin to take over, and eventually we have a leukemia that is completely resistant,” explains Dr. Jiang.
What this means, says Dr. Connie Eaves, Director of the BC Cancer Agency’s Terry Fox Laboratory, is that for many CML patients, Gleevec probably won’t on its own be able to kill off all the cancer cells.
"We didn’t anticipate that, even for such targeted therapies, we would need a combination of approaches to successfully eradicate the disease,” says Dr. Eaves. “This means that Gleevec isn’t adequate and we therefore need to find additional therapies that may be more effective than Gleevec alone.”
What does this new information mean for patients with CML? “This is such an important observation,” says Dr. Donna Forrest, Member of the Leukemia/BMT Program of BC. “While the vast majority of patients with CML in chronic phase receiving Gleevec therapy continue to do well, the fact that the leukemic stem cells are mutating and in some cases leading to Gleevec resistance, means that new efforts need to be directed at developing specific therapies to target these stem cells if we are going to be able to ‘cure’ this disease.”
The BC Cancer Foundation provides core funding for research at the BC Cancer Agency. Funding for this research was also provided by the Canadian Cancer Society and the Terry Fox Foundation, from the Leukemia and Lymphoma Society of Canada, the Michael Smith Foundation for Health Research, the Cancer Research Society, Genome BC, and the USA National Institutes of Health.
The BC Cancer Agency, an agency of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer, and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care.
For more information, please contact:
Nicole Adams
Director, Communications
BC Cancer Agency
Tel: 604.675.8105
Pgr: 604.641.5167
nadams@bccancer.bc.ca
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