Synergistic effect of two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used as single-agent therapy, is identified by a study, a collaboration between Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow, published in the journal Nature Communications.
"Our study shows that two types of drugs, MDM2 inhibitors and BET inhibitors, work synergistically to promote significant anti-leukemia activity. The results were surprising because previous research had shown that each drug on its own had modest benefit against AML. The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML", says Peter Adams, Ph.D., a professor at Sanford Burnham Prebys and senior author of the study.
Adult acute myeloid leukemia (AML) is a type of blood and bone marrow cancer where the bone marrow produces abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. This condition may worsen quickly if untreated.
There are many types of AML, each having different chromosome changes, gene mutations and epigenetic modifications. This makes it difficult to find novel therapies that would target particular type. According to the American Cancer Society, the five-year survival rate for adults with AML remains less than 30%.
TP53 is the most commonly mutated gene in all human cancers. This gene remains unaltered in about 90% of AML patients. The product of the TP53 gene - p53, acts to suppress the tumors. This reinvents the need to design drugs that can reactivate or boost its anti-cancer powers in AML, providing a clinical benefit.
"Our research unexpectedly showed that like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway. BET inhibitors mute the power of a protein called BRD4, which we found is a p53 suppressor in AML. Between the two drugs, you end up with a 'double whammy' effect that fully unleashes the anti-cancer activity of p53. Better therapies for AML are desperately needed. This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease", says Adams.