While most patients with chronic myeloid leukemia (CML) show a remarkable response to Gleevec, a small number eventually develop resistance to the drug. A new preclinical study out of the Oregon Health & Science University Cancer Institute may prove to be useful in counteracting and even preventing such resistance.
Researchers found that combining Gleevec with a new CML drug designed to combat Gleevec resistance produced more activity against leukemia cells than using either drug alone. The study was published in the Oct. 1 issue of Clinical Cancer Research.
"Supplementing Gleevec with a second drug that targets Gleevec-resistant cells has the potential to eliminate resistant cells before they can expand and cause problems," said study lead author Thomas O'Hare, Ph.D. "Our results suggest that a combination of drugs is feasible for minimizing resistance to Gleevec."
The new drug being tested in combination with Gleevec, dasatinib (BMS-354825), is now in clinical trials and is showing significant activity in patients with resistance to Gleevec.
"We wanted to see what would happen if we combined Gleevec with this new drug," said Brian Druker, M.D., who developed Gleevec in collaboration with Novartis scientists for the treatment of CML. Gleevec is the first drug to demonstrate that a therapy targeted to the specific molecular defect can be effective in real patients. Druker holds the JELD-WEN chair of leukemia research at the OHSU Cancer Institute and is a Howard Hughes Medical Institute investigator.
Gleevec stops the leukemia by targeting a specific enzyme within cells that causes them to become cancerous. If the enzyme is a lock, then Gleevec is the key that fits into the lock, stopping the cancer. When cancer cells become resistant, it's as if the lock has changed slightly. Gleevec still fits into the lock loosely, but can't stop the mutated cancer. Dasatinib fights Gleevec-resistant CML by fitting into the same lock as Gleevec, and in mutated cancer cells, fits even better than Gleevec.
"Our concern with the combination was whether two keys, Gleevec and a companion drug, would block each other when administered at the same time," Druker said. "Much to our delight, we found that not only did they not block one another, but the combination performed better than either drug alone."
Some CML patients living today began taking Gleevec in a clinical trial as many as seven years ago. "This study gives us reason to believe that CML might be controlled in patients for even longer periods of time, potentially much longer," Druker said. Clinical trials of Gleevec in combination with dasatinib are already in the planning stages.
"Molecularly targeted therapies are new," said O'Hare, a research scientist in Druker's OHSU Cancer Institute/HHMI laboratory. "We are learning to optimize them in the face of drug resistance. If this combination therapy does work well in CML clinical trials, the benefits of anticipating and cutting off all escape routes as early as possible should have application in other targeted cancer therapies as well."
Gleevec is the world's first anti-cancer therapy to successfully target only cancer cells while leaving normal cells alone, resulting in a treatment that is extremely effective with little or no side effects. The U.S. Food and Drug Administration's May 2001 approval of the drug was the fastest ever for an anti-cancer therapy.
CML is a fatal disease that affects about 6,000 people in the United States every year. Virtually all CML patients treated with Gleevec have experienced blood counts that have returned to normal. In 75 percent of these patients, leukemia cells can no longer be detected. With four years of follow-up, only 16 percent of patients have developed resistance.
In addition to O'Hare and Druker, study authors include Denise K. Walters, Ph.D., Michael W.N. Deininger, M.D., Eric P. Stoffregen, and Daniel W. Sherbenou, OHSU Cancer Institute; and Michael C. Heinrich, M.D., Portland Veterans Affairs Medical Center.
About the OHSU Cancer Institute
The OHSU Cancer Institute is the only National Cancer Institute-designated cancer center between Sacramento and Seattle. It comprises some 120 clinical researchers and basic scientists who work together to translate scientific understanding into longer and better lives for people living with cancer. In the lab, basic scientists examine cancer to uncover molecular abnormalities that cause disease. This basic science is empowered by more than 200 open clinical trials that test in patients what's been proved in the laboratory. Visit ohsucancer.com for more information about the OHSU Cancer Institute.