Drugs that target the cancer-promoting proteins MDM2 and BET have been tried in acute myeloid leukemia (AML) and haven't been all that effective on their own. But what if they were combined?
Researchers at the Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow have early evidence a combination strategy may, in fact, work in AML.
Combining MDM2 and BET inhibitors improved the killing of AML cell lines in lab studies and was more effective than solo treatment in eradicating the cancer in mouse models, the researchers reported in the journal Nature Communications. The combination seems to work by activating the tumor-suppressing protein p53, they reported.
“The results were surprising because previous research had shown that each drug on its own had modest benefit against AML,” said senior author Peter Adams, Ph.D., a professor at Sanford Burnham Prebys, in a statement. “The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML.”
The gene TP53 produces the protein p53, a known tumor suppressor. TP53 is frequently mutated across a range of cancers, which is why targeting the gene is a popular pursuit in oncology research.
Until now, the popular thinking was that MDM2 inhibitors activate p53. BET inhibitors, on the other hand, suppress leukemia-associated genes but don’t 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 discover that BET inhibitors actually do activate p53—by suppressing another protein called BRD4. Combining MDM2 and BET inhibition produces “a 'double whammy' effect that fully unleashes the anti-cancer activity of p53,” Adams said.
The Sanford Burnham Prebys-led team went on to test the combination in two mouse models of AML. In both cases, inhibiting BET and MDM2 together outperformed either mechanism on its own in eradicating the cancer and extending survival, the researchers reported.
The biopharma industry continues to show an interest in both BET and MDM2 inhibitors, though development efforts have run into some obstacles.
In 2019, Roche dropped a phase 1 BET inhibitor from its pipeline. And last April, the Swiss pharma giant stopped testing MDM2 inhibitor idasanutlin in a phase 3 AML trial after a combination of the drug with cytarabine proved disappointing. Early trials of idasanutlin in combination with Roche’s AML drug Venclexta are underway.
Meanwhile, other early-stage BET and MDM2 inhibitors have driven some deal-making in biopharma. In 2018, Aptose Biosciences teamed up with Ohm Oncology to advance a BET inhibitor in hematologic cancers. And last September, Rain Therapeutics licensed an MDM2-targeted drug from Daiichi Sankyo and raised $63 million to take it into pivotal trials in differentiated or dedifferentiated liposarcoma.
The Sanford Burnham Prebys and University of Glasgow researchers noted in their study that the heterogeneity of AML makes it a particularly difficult disease to address with targeted treatments. While many different genes can be mutated to drive the disease, no single mutation is dominant in a majority of patients.
But 90% of AML tumors have TP53, “suggesting that human AML subtypes employ alternative mechanisms to inactivate the p53 pathway.”