Combining sorafenib with obatoclax rather than administering either drug alone may represent a novel and potentially effective treatment strategy for acute myeloid leukemia (AML).
Sorafenib, already approved by the FDA for use against kidney and liver cancers, recently has been shown to kill other malignant cells, including AML cells—particularly those with a specific mutation in the FLT3 protein. Obatoclax is being tested as a treatment for various blood cancers.
Prior research has indicated that the two agents might enhance each other’s activity because they inhibit complementary survival pathways in leukemia cells. Both sorafenib and obatoclax inhibit the protein Mcl-1, but do so through different mechanisms. Mcl-1 has been shown to prevent apoptosis (programmed cell death) in various cancer cells.
To investigate further, Steven Grant, MD, of the oncology research program at Virginia Commonwealth University in Richmond, and colleagues tried the combination therapy in AML cells. As the team reported in the journal Blood, the treatment caused profound cell death and mitochondrial injury, as well as prolonged survival in animal models, with only limited toxicity in healthy tissue. The combination nearly abolished Mcl-1 expression in AML cells, activating or increasing levels of three proteins that contribute to AML cell apoptosis.
With the help of the immunosuppressant chloroquine, the combination therapy increased AML cell death even further by inhibiting autophagy, a process that diverts energy from the cell’s own less critical constituents in order to enhance its survival.