Drug Blocks Gene Mutation Effect In Lethal Leukemia

A new drug blocks the impact of a cancer-causing gene mutation found in a common and lethal form of leukemia, say researchers at the Johns Hopkins Kimmel Cancer Center.

Their findings in animal and test tube models are featured in today's issue of Blood.

Clinical trials to test the safety and effectiveness of the drug, CEP-701, in adult patients who have relapsed or stopped responding to standard therapy, and who have the mutations, are now under way.

CEP-701 appears to cancel out the effect of mutations of the FLT3 gene, first isolated by the Kimmel Cancer Center team in 1992 and shown to be a primary culprit in an aggressive, treatment-resistant form of acute myeloid leukemia (AML). Approximately 40 percent of AML patients have FLT3 mutations, and most of them will not be cured using current therapies, according to the Hopkins experts.

"Right now, AML patients with FLT3 mutations have a dismal diagnosis with little hope of cure. We hope to change that with this new drug," says Donald Small, M.D., Ph.D., associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and study director. "Since it selectively targets the genetic error, CEP-701 turns it from a negative indicator to a positive one. This is what molecular medicine is all about, finding the cellular mistakes that work against us to cause cancer and turning them to our advantage to kill the cells," says Small.

The investigators tested CEP-701 in mouse cell lines and human AML cells with FLT3 mutations and found the drug interfered with the signal of the altered gene and led to leukemia cell death. Ultimately, the investigators believe cures will be obtained by combining the new drug with chemotherapy. However, they must first test the drug's safety and effectiveness alone before they can combine it with other anti-leukemia drugs, Small said.

CEP-701 is one of a new class of drugs called tyrosine kinase inhibitors, so-called because of their ability to block specific cell signaling proteins. "Mutant FLT3 uses its tyrosine kinase portion to signal leukemia cells to grow and also to prevent them from dying," explains Mark Levis, M.D., Ph.D., assistant professor of oncology at the Hopkins Kimmel Cancer Center and the paper's first author. "By inhibiting the gene's ability to communicate with cells, we can slow the growth and promote the death of AML cells. In essence, we render the gene powerless. It's as if it never existed," he says.

The investigators also have developed a test to identify FLT3 mutations in AML patients. Adult patients who have been diagnosed with AML may contact Doug Smith, M.D. at (410) 614-5068 or Small at (410) 614-0994 to arrange for the test and to learn if they are candidates for the trial.