Novel Drug Combination Serves as Potential Treatment for Acute Myeloid Leukemia

MDM2 inhibitors and BET inhibitors, which show limited efficacy against acute myeloid leukemia (AML) as monotherapies, are potent against AML when used in combination, according to a study published in Nature Communications. The researchers said they were able to significantly enhance cancer cell death through the joint administration of these 2 drugs, compared with their partial efficacy as single-agent therapies.

According to the investigators, TP53, the most frequently mutated gene in all human cancers, remains unaltered in approximately 90% of patients with AML. P53, the product of the TP53 gene, acts to suppress tumors, leading researchers to seek out drugs that would reactivate or boost its cancer fighting abilities in AML for clinical benefit.

“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,” said Peter Adams, PhD, in a press release. “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. Between the two drugs, you end up with a 'double whammy' effect that fully unleashes the anti-cancer activity of p53.”

Because there are multiple types of AML, and different cases have different chromosome changes, gene mutations, and epigenetic modifications, it is difficult for researchers to find novel therapies that will work for a substantial population of patients. The 5-year survival rate for adults with AML remains under 30%, despite considerable progress toward finding effective treatments in recent years.

“Better therapies for AML are desperately needed,” Adams said. “This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease.”

REFERENCE

New drug combination shows promise as powerful treatment for AML [news release]. EurekAlert; January 19, 2021. Accessed July 28, 2021. https://www.eurekalert.org/news-releases/922263