The results of the study appear in the July 16, 2004 issue of the peer-reviewed journal Science, published by the American Association for the Advancement of Science, the world's largest general scientific organization. Early phase human studies of the experimental therapy, taken in pill form like Gleevec, already are underway at the Jonsson Cancer Center in patients who have developed a resistance to Gleevec.
About 15 to 20 percent of CML patients who take Gleevec become resistant to the drug and suffer a relapse, leaving them with few effective treatment options, said Dr. Neil Shah, an oncologist and researcher, an assistant professor of hematology/oncology and the study's first author. In patients with resistant disease, secondary mutations in the gene linked to CML allow the cancer to evade therapy. It is those mutations that are targeted by the new compound, BMS-354825, being developed by Bristol-Myers Squibb.
"Learning from what happens when a drug fails in some patients can lead to a new treatment paradigm," Shah said. "In the future, we may be combining therapies that can, amongst them, override all the resistance mechanisms that allow cancer to evade individual therapies. In the future, cancer may be treated similarly to HIV, with a cocktail of drugs."
Gleevec targets a mutant cancer-causing protein linked to CML, which each year strikes more than 10,000 adults worldwide. Specifically, Gleevec is a tyrosine kinase inhibitor, one of a new class of drugs that can interfere with cell signaling pathways implicated in tumor development. Much of the pioneering work done to link the gene and its mutant protein to CML was performed at UCLA's Jonsson Cancer Center.
In some patients, secondary mutations in the CML-linked gene arise that prevent Gleevec from binding to its intended target. These mutations, because they then operate unchecked, cause the leukemia to recur.
Dr. Charles Sawyers, a professor of hematology/oncology, an investigator with the Howard Hughes Medical Institute and the senior author of the study, said this work could represent a major advance for the patients who suffer a relapse on Gleevec.
"Gleevec remains a spectacular step forward in the application of targeted therapy to CML specifically, and serves as a model for how to do this more generally in cancer," Sawyers said. "However, some CML patients develop resistance to Gleevec after several years of therapy. Structural modeling studies predicted that other inhibitors that bind to the target protein differently from Gleevec should work against these mutants. This paper reports the effectiveness of such an inhibitor in Gleevec resistant cells in tissue culture and in mice."
Shah and Sawyers are hopeful that the experimental inhibitor will prove effective in human patients as well. Future studies may eventually pair Gleevec with this new inhibitor, if it proves to be safe and effective in clinical trials.
"We hope this represents another viable treatment option for patients with this disease," Shah said. "There may now be hope beyond Gleevec should their disease relapse."
Shah said the drug also may be useful for treating other diseases that respond to Gleevec initially, such as gastrointestinal stromal tumors.
The research, conducted at UCLA's Jonsson Cancer Center, was funded in part by the Howard Hughes Medical Institute and the Leukemia & Lymphoma Society of America.
UCLA's Jonsson Comprehensive Cancer Center is made up of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, is dedicated to promoting cancer research and applying the results to clinical situations. In 2004, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for five consecutive years.
For more information on the Jonsson Cancer Center, visit our web site at www.cancer.mednet.ucla.edu.
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Science