Drugs that target the MDM2 and BET – cancer – promoting proteins have been tested in acute myeloid leukemia (AML) and were less effective on their own. But what if they were put together?
Researchers at the Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow have early evidence that a combination strategy could, of course, work in AML.
The combination of MDM2 and BET inhibitors improved the killing of AML cell lines in laboratory studies and was more effective than single-handled treatment in cancer eradication in mouse models, the researchers reported in the journal Nature Communications. The mixture appears to work by activating the tumor-depleting protein p53, they reported.
“The results were remarkable because previous research had shown that each drug alone had little to gain against AML,” lead author Peter Adams, Ph.D., a professor at Sanford Burnham Prebys, said in recitation. “The new research provides a scientific philosophy to advance clinical studies of the drug mix in patients with AML.”
The TP53 gene expresses the protein p53, a well-known tumor suppressor. TP53 is often overlapped across a range of cancers, which is why targeting the gene is a popular pastime in oncology research.
Until now, the popular idea was that MDM2 protectors activated p53. BET inhibitors, on the other hand, suppress leukemia-related genes but do not affect p53, researchers believed.
Adams and his team tested MDM2 and BET inhibitors in AML cell lines and samples from patients. They were surprised to find out that BET inhibitors actually activate p53 – by eliminating another protein called BRD4. Combining MDM2 and BET inhibition produces a “dual whammy effect” that completely releases p53 anti-cancer activity, ”Adams said.
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The team led by Sanford Burnham Prebys went on to test the combination in two mouse models of AML. In each case, by blocking BET and MDM2 together they did better than one device alone in eradicating the cancer and extending survival, the researchers said.
The biopharma industry continues to show interest in BET and MDM2 protectors, although development efforts have been a hurdle.
In 2019, Roche released a BET level 1 inhibitor from its pipeline. And last April, the Swiss pharma giant stopped testing the idasanutlin MDM2 inhibitor in a level 3 AML test after a combination of the drug with cytarabine became a disappointment. Early trials of idasanutlin in combination with the AML Roche drug Venclexta are ongoing.
Meanwhile, other early BET and MDM2 inhibitors have done some work in biopharma. In 2018, Aptose Biosciences teamed up with Ohm Oncology to promote a BET inhibitor in hematologic cancers. And last September, Rain Therapeutics approved a MDM2 targeted drug from Daiichi Sankyo and raised $ 63 million to bring it into basic tests in differentiated or dedifferentiated liposarcoma.
Researchers Sanford Burnham Prebys and the University of Glasgow noted in their study that the heterogeneity of AML makes it a very difficult disease to treat with targeted treatments. Although many different genes can be passed on to transmit the disease, a majority of patients do not have a single mutation.
However, 90% of AML tumors contain TP53, “suggesting that human AML subtypes use other methods to activate the p53 pathway.”