"While Gleevec represents a major treatment advance for CML – approximately 95 percent of patients treated with Gleevec achieve remission – there clearly is a need for therapies that produce longer remissions, are active against advanced disease, and can be used when Gleevec loses effectiveness," says Dana-Farber's James Griffin, MD, senior author of the study. "The goal of this study was to develop a drug that hits the same target on CML cells as Gleevec does, and to hit more of the target."
Gleevec shuts down CML by blocking the function of Bcr-Abl, the abnormal tyrosine kinase protein in the leukemic cells that causes them to grow too quickly. However, it does not bind very tightly to this protein, takes a long time to induce remissions, and patients can develop a resistant type of Bcr-Abl that no longer binds to Gleevec at all.
To circumvent these shortcomings, researchers at Novartis determined the crystal structure of Bcr-Abl, and then constructed compounds that would lock into the receptor more securely than Gleevec. Investigators at Dana-Farber tested the new compounds to measure their effectiveness against CML in laboratory cell cultures and mice with the disease.
The final product was AMN107, a half-new, half-old hybrid. Half of AMN107's chemical makeup is identical to a portion of Gleevec, the remainder is completely different, explains Griffin, who is also a professor of medicine at Harvard Medical School.
In experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were minimal.
"In these pre-clinical tests, the new drug was very impressive," says Griffin. "We've been able to expand on what we learned from Gleevec to produce a therapy that, thus far, has a more powerful and enduring impact against CML."
AMN107 has been started in early phase clinical trials at M.D. Anderson Cancer Center, and if it proves safe to administer, will be tested for effectiveness in CML patients at Dana-Farber and other sites. If the drug is effective, the next task will be to determine the optimal way of using it –– whether alone or in combination with Gleevec or as a follow-up to Gleevec. Studies are also under way to learn whether AMN107 is effective against other diseases, such as gastrointestinal stromal tumor (GIST), for which Gleevec has become a reliable treatment.
"We're very encouraged by the results so far," Griffin remarks. "This is an elegant example of how rational drug design –– developing drugs based on a molecular understanding of cell structures and processes –– can be used to attack human diseases."
The findings contribute to a larger Dana-Farber research effort, dubbed the "Kinase Project," which seeks to identify abnormal tyrosine kinases -- enzymes that spark or halt growth -- in cancer cells and test agents known to act against them.
The study's lead author is Ellen Weisberg, PhD, of Dana-Farber. Co-authors include researchers at Dana-Farber, Novartis, Brigham and Women's Hospital, and Children's Hospital Boston.
Funding for the study was provided by the National Institutes of Health, the Leukemia and Lymphoma Society, and the Burroughs Wellcome Fund.
Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Journal
Cancer Cell