The drug was powerful in its own right, the researchers say, but they found that some acute myeloid (AML) cells were themselves resistant to ABT-737, so they added another drug that knocked out this secondary resistance. Together, these agents may provide a powerful therapy against AML, and could form the basis of a new way to treat the cancer, say the scientists.
“The combination of these two experimental drugs provides the highest synergistic action I have ever seen against acute myeloid leukemia cells,” said Michael Andreeff, professor in the center’s departments of stem cell transplantation and leukemia.
In this study, researchers found that ABT-737 “potently” kills AML cell lines as well as blast cells taken from AML patients. ABT-737 targets BCL-2, which is a cell ‘survival’ protein that is over-expressed in many types of cancer. This protein prevents a cell from committing apoptosis (cell death) by latching on to other BCL-2 family member proteins, rendering them ineffective.
However, AML cells in which another a protein known as MCL-1 is over expressed did not die, which makes this protein a “resistance factor” to ABT-737 and to standard chemotherapy, Mr Andreeff said.
The researchers added an experimental drug, a MAP-kinase inhibitor, to knock down MCL-1 expression, and found that this inhibitor also worked to inhibit cells in which BCL-2 is phosphorylated, which can switch a protein on or off. “ABT-737 had diminished effects against cells with phosphorylated BCL-2, which was restored by combination with a MAPK inhibitor,” Mr Andreeff said.
MD Anderson Cancer Center said that the next step is to test ABT-737 in patients with leukemias.