BALTIMORE – June 3, 2002 -- Researchers have shown in mice that a new drug blocks the effect of a cancer-causing gene mutation found in a lethal form of leukemia according to a new study.
An early clinical trial to test the drug’s safety in humans is under way, and may offer increased survival for patients with acute myeloid leukemia (AML) and a genetic mutation of a gene called, FLT3, the combination of which is almost always fatal.
The researchers led by Dr. Donald Small of the Johns Hopkins Kimmel Cancer Center published their findings in animal and test tube models in the June 1, 2002, issue of Blood.
"Right now, AML patients with FLT3 mutations have a dismal diagnosis with little hope of cure,” Small said in a prepared statement.
“We hope to change that with this new drug. 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 study director Small, who is also associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical School.
AML, which is characterized by uncontrolled growth of marrow cells (myeloid cells) in the blood and bone marrow, strikes more than 10,000 adults and children each year in the U.S. It is the most common form of adult leukemia and the second most common type of childhood leukemia.
The investigators tested CEP-701 in leukemic cells with the FLT3 gene mutation taken from mice and human AML cells with FLT3 mutations. The mutated form of FLT3 produces a signal that stimulates the cell division machinery into action, spurring the cell to begin uncontrolled cell division.
They found the drug (CEP-701) interfered with the signal of the altered gene, which in turn shut down the duplication machinery and ultimately led to the deaths of the leukemic cells.
While it has yet to be tested in humans, the investigators believe the drug may provide cures when combined 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 to signal leukemia cells to grow and also to prevent them from dying," explains Dr. Mark Levis, an 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 (mutant) gene powerless. It's as if it never existed," he says.
A clinical trial to test the safety and effectiveness of CEP-701 in adult patients who have relapsed or stopped responding to standard therapy, and who have the FLT3 mutation is now under way.
The investigators also have developed a test to identify FLT3 mutations in AML patients. Adult patients who have been diagnosed with AML may contact Dr. Doug Smith 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.
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