LA JOLLA, CALIF. - Jan 20, 2020 - Scientists have identified two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used alone. The researchers were able to significantly enhance cancer cell death by jointly administering the drugs that are only partially effective when used as single-agent therapies. The study, a collaboration between Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow, was recently 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," says Peter Adams, Ph.D., a professor at Sanford Burnham Prebys and senior author of the study. "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."
There are many types of AML, and different cases have different chromosome changes, gene mutations and epigenetic modifications, making it difficult for researchers to find novel therapies that will work for a substantial proportion of patients. Although much progress has been made toward finding effective treatments in recent years, the long-term overall survival has stagnated. According to the American Cancer Society, the five-year survival rate for adults with AML remains less than 30%.
Notably, TP53, the most frequently mutated gene in all human cancers, is found unaltered in about 90% of AML patients. Since the product of the TP53 gene, p53, acts to suppress tumors, scientists have sought drugs that reactivate or boost its anti-cancer powers in AML, which should provide a clinical benefit. However, such drugs on their own have been disappointing in AML.
"We were interested in combining MDM2 and BET inhibitors because each showed encouraging pre-clinical activity, but limited activity when given to patients as a single agent," says Adams. "Previous research had shown that MDM2 inhibitors activate p53, and BET inhibitors suppress genes associated with leukemias--but not p53.
"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," says Adams. "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," adds Adams. "This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease."
The first authors of the study are Anne-Louise Latif and Ashley Newcombe of the University of Glasgow. Additional authors include Andrew Davis, Xue Lei and Sha Li of Sanford Burnham Prebys; Helen Stewart and Tim Chevassut of the University of Sussex; William Clark, Jennifer Morton, Lynn McGarry, Kevin M. Ryan and Jun-Ichi Sakamaki of the Beatson Institute (Glasgow); Claire McKeeve of Queen Elizabeth University Hospital (Glasgow); Brian Higgins of the Roche Innovation Center (New York); Sheela Abraham, Karen Blyth, Joana Campos, John Cole, Mhairi Copland, Kathryn Gilroy, Tessa Holyoake, Xu Huang, Karen Keeshan, Kristina Kirschner, Jonathan Lopez, Loveena Rishi, Neil Robertson, Stephen Tait and Maria Terradas of the University of Glasgow.
The study's DOI is 10.1038/s41467-020-20378-8.
This work was funded by CRUK program grant C10652/A16566, The Children with Cancer UK, the Howat Foundation, the Wellcome Trust (grant number 105641/Z/14/Z), the Sussex Cancer Fund, the CRUK Glasgow Centre (A25142), Core Services at the Cancer Research UK Beatson Institute (A17196), the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and the Chief Scientist's Office, Scotland, and the Sussex Cancer Fund.
About Sanford Burnham Prebys Medical Discovery Institute
Sanford Burnham Prebys is a preeminent, independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 40 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children's diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.