UC hematology experts present research at national conference

IRAK4 is a protein known to help drive growth of acute myeloid leukemia (AML) cells through overactivation, making it a potential target for new treatments. Unfortunately, initial trials suggest treatments that target the protein may have limited effect on their own (as monotherapy). 

Cancer Center researcher Eric Vick, MD, PhD, and colleagues sought to identify which target would be most effective at killing cells after being weakened by the reduction of the protein. 

“After you have combined the loss of IRAK4 with different pharmacologic agents, you create a situation that is lethal for the cells,” said Vick, a clinical fellow working in Daniel Starczynowski’s lab at Cincinnati Children’s who will join UC’s faculty in January. 

Vick said the team tested more than 2,400 small molecules to compare their effectiveness in killing normal AML cells and those that did not have overactive IRAK4. They found one compound was especially effective at killing AML cells by reducing the levels of a different protein called c-myc that drives cancer growth.

“It degrades c-myc using the cell’s machinery, and as a result, we’re able to drop the levels of c-myc to a point where the cells can’t survive,” Vick said. “Many cancer cells rely on high levels of c-myc in order to survive, so part of what we’ve been studying is how much AML requires for survival. The loss of IRAK4 signaling allows a faster and lower reduction than would normally be possible in these cells.”

Many drugs have been developed to target c-myc without much clinical success, so Vick said moving forward the team will test the use of this class of drugs with IRAK4 inhibitors as an alternative approach to target leukemia.

“What we’re hoping to do is create a situation where we can sensitize patients with leukemia with a relatively mild, very tolerable drug — the IRAK4 inhibitor — and then treat with a second, more robust drug that can wipe out all the leukemia cells,” he said. “As always, we’re trying to extend remissions and develop a cure.”

More than 30% of acute myeloid leukemia (AML) patients have a mutation that helps the cancer grow and thrive. There are currently available medications that target this mutation that are effective, but tumor cells often develop additional mutations that lead to drug resistance. 

Researchers including Ola A. Elgamal, PhD, in the Cancer Center’s Leukemia and Drug Development Lab are developing new therapies to overcome this drug resistance and make treatments more effective. Elgamal and colleagues particularly focused on targeting the most common mutation that leads to resistance, known as a “gatekeeper” mutation.

The research team tested a new compound in the lab and found it works “very well” against the gatekeeper mutation and shows promise as a treatment that could help lead to long-term survival for patients with AML. A Phase 1 clinical trial in healthy volunteers is currently underway to determine the best dose of the treatment in humans, Elgamal said.

“That will allow us to move forward and test it in AML patients that have a positive mutation,” said Elgamal, assistant professor in the UC College of Medicine’s Division of Hematology/Oncology. “We are also using some novel animal models to understand how the immune system contributes to the prolonged response to this type of therapy.”