June 18, 2002
New "targeted" drug gains success against form of Leukemia in laboratory study
David Fisher, MD, PhD
Spurred by the success of Gleevec - a drug that has rescued many patients with chronic myelogenous leukemia by targeting weak points in their cancer cells - scientists at Dana-Farber Cancer Institute report that another such "smart" drug kills certain acute myelogenous leukemia (AML) cells in test-tube samples and in mice.
The drug, known as PKC412, proved effective in laboratory and animal studies and is now being tested in a clinical trial for some patients whose AML has resisted other treatments, says Dana-Farber's Ellen Weisberg, PhD, lead author of a study being published in the June issue of Cancer Cell and on the journal's Web site.
The trial, being run by Dana-Farber/Partners CancerCare, Memorial Sloan-Kettering Cancer Center, and M.D. Anderson Cancer Center, "will help determine whether PKC412 is effective in AML patients whose bone marrow cells have a particular genetic mutation," Weisberg observes. "If it is effective, PKC412 could take its place alongside Gleevec in a new class of drugs that destroy cells with specific abnormalities while leaving other cells unharmed."
An estimated 10,600 people in the United States will be diagnosed with AML in 2002, and another 7,400 are expected to die from the disease, according to the American Cancer Society.
PKC412 zeros in on a defect in a cell structure called the FLT3 tyrosine kinase receptor. When the receptor is working correctly, it helps ensure that blood-making cells in the bone marrow proliferate and mature properly. When it's defective, because of a genetic mutation, the cells grow out of control and fail to perform their normal function, resulting in AML.
"By finding a drug that inhibits the mutated form of FLT3, you can specifically target these leukemia cells," remarks Weisberg, who also is an instructor in medicine at Harvard Medical School.
It has been shown that 30 percent of people with AML have a mutation in the gene for FLT3. Weisberg and her colleagues screened dozens of compounds that are known to act against another tyrosine kinase receptor closely related to FLT3.
They found that when AML cells with mutant FLT3 were exposed to PKC412, the cells died. When they gave the drug to leukemic laboratory mice with mutant FLT3, all the animals were cured.
Further tests confirmed that the results were no coincidence, that abnormal FLT3 is indeed the target of PKC412.
Preliminary clinical studies with PKC412 indicate that it does not produce serious side effects. As a result, it could go directly into a Phase II trial to test its effectiveness against AML.
James Griffin, MD
If PKC412 proves successful, it could provide an important addition to medicine's arsenal against AML, says the study's senior author, James Griffin, MD, of Dana-Farber. While many younger patients can be successfully treated for AML, patients over age 60, as well as those who develop AML as a result of previous cancer treatment, tend to fare poorly.
"The major chemotherapy drugs used as initial therapy for AML have not changed in more than 25 years," notes Griffin, who also is a professor of medicine at Harvard Medical School. "PKC412, and the targeted approach it represents, have the potential to make significant inroads against this disease."
The paper's other authors are Christina Boulton and Louise Kelly, PhD, Brigham and Women's Hospital (BWH); Paul Manley, Doriana Fabbro, and Thomas Meyer, Novartis Pharma, Basel, Switzerland; and D. Gary Gilliland, MD, PhD, Dana-Farber and BWH.
The study was supported by grants from the National Institutes of Health and the Leukemia and Lymphoma Society.
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.
