Combining birinapant with a p38 inhibitor is a promising therapeutic regimen for patients with acute myeloid leukemia (AML), according to data presented in a report published in Cancer Cell. Birinapant is currently in clinical trials.1
In this study, researchers sought to enhance the anticancer effects of birinapant, which is a SMAC-mimetic. SMAC is a pro-apoptotic molecule. The researchers, from the Walter and Eliza Hall Institute in Parkville, Victoria, Australia, screened kinase inhibitors for ones that increased the production of tumor necrosis factor (TNF) in cells that were treated with birinapant. Inhibitors of p38 were found to overcome the resistance of primary AML to birinapant.
Both birinapant and p38 inhibitors have been studied alone in clinical trials for treating cancer, offering hope that the combination could be safely given to people with AML who have few other treatment options.
The team was excited to discover that the combination of p38 inhibitors and birinapant had a much stronger anticancer effect than either agent alone.
“Both p38 inhibitors and birinapant have been safely used in humans in clinical trials,” said Najoua Lalaoui, PhD, of the Hall Institute, and first author on the study. “We are hopeful that the combination of these agents could be an effective anticancer treatment.”
Many people with AML respond poorly to treatment, with fewer than one-third surviving for 5 years after their diagnosis. The current treatment for AML is high-dose chemotherapy, but it has many toxic side effects.
“Our findings have made us hopeful that a combination of birinapant and a p38 inhibitor may be more effective in treating AML than current therapies, and also have less toxicity for patients,” Lalaoui said. “We tested forms of AML that are highly resistant to chemotherapy and found that birinapant and p38 inhibitors could even kill these cancer cells, which is great news.”
“Birinapant has been used in clinical trials for several types of cancers. Our latest research is part of an exciting next step, fine tuning how birinapant can be used in the clinic to enhance its anticancer effects,” said John Silke, PhD, and corresponding author on the study. Birinapant is being developed by TetraLogic Pharmaceuticals Corporation based in Malvern, Pennsylvania.
The research team worked closely with a community representative named Pam through the Walter and Eliza Hall Institute’s consumer-researcher buddy system.
“The involvement of Pam in this project provided us with invaluable feedback and review, and opportunities to discuss our ideas with someone who has a personal experience of cancer,” Lalaoui said.
1. Lalaoui N, Hänggi K, Brumatti G, et al. Targeting p38 or MK2 enhances the anti-leukemic activity of smac-mimetics. Cancer Cell. 2016;29(2):145-158.