Combining two potential cancer therapies with distinct modes of action and limited clinical benefits on their own resulted in powerful anti-cancer activity in both cellular and mouse models of acute myeloid leukemia (AML), a study shows.
Notably, these benefits were found to be associated with the stabilization of p53 — a tumor suppressor protein — by one therapy, and the blocking of BRD4, a previously unsuspected repressor of p53 target genes, by the other. Together the therapies boosted p53’s anti-cancer effects.
“Our study shows that two types of [therapies], MDM2 inhibitors and BET inhibitors, work synergistically to promote significant anti-leukemia activity,” Peter Adams, PhD, the study’s senior author and a professor at Sanford Burnham Prebys Medical Discovery Institute, in California, said in an institute press release.
“The results were surprising because previous research had shown that each [therapy] on its own had modest benefit against AML,” Adams added, noting that these findings provide “scientific rationale to advance clinical studies of the [therapy] combination in patients with AML.”
The study, “BRD4-mediated repression of p53 is a target for combination therapy in AML,” was published in the journal Nature Communications.
Despite recent treatment advances, the estimated five-year survival rate of adults with AML in 2019 remained below 30%. This is partly due to its high genetic, molecular, and medical variability, posing “a significant obstacle to finding novel targeted agents with a broad therapeutic reach,” the researchers wrote.
“One key unifying feature of AML, that could potentially be exploited to benefit many patients, is that the majority of cases exhibit [a normal] TP53 [gene],” they added.
One of the most frequently mutated genes in human cancer, TP53 provides instructions to produce p35, a natural tumor suppressor protein that cells use to prevent uncontrolled growth. While 90% of AML patients have no TP53 gene mutations, the produced p53 protein is commonly inactivated by other mechanisms, including the overproduction of its suppressors, MDM2 and MDM4.
MDM2 inhibitors, or those that work by suppressing the activity of MDM2, have been previously tested in clinical trials of AML patients, but with limited benefits. By preventing MDM2 from interacting with p53, MDM2 inhibitors were expected to increase p53 stability, which would activate signaling pathways that limit cell growth and eventually kill cancer cells.
Further preclinical data has suggested that combining MDM2 inhibitors with other standard cancer therapies may be more effective in AML. Still, some early clinical trials failed to show benefit with some of these combinations.
Now, a collaborative study between researchers at Sanford Burnham Prebys and at the University of Glasgow found that combining MDM2 inhibitors with a particular type of potential cancer treatment, called BET inhibitors, could achieve these wanted benefits.
BET inhibitors work by blocking the activity of bromodomain and extraterminal (BET) proteins, such as BRD4. BRD4 plays a role in the activation of genes involved in cell growth, most notably c-MYC, which is overly activated in AML.
While preclinical studies demonstrated that BRD4 suppression was effective across a range of AML subtypes, the efficacy of BET inhibitors as a single therapy in AML patients has been modest, the researchers noted.
“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,” Adams said.
The researchers found that the combination therapy resulted in superior anti-cancer effects than either therapy used alone in cells collected from 15 AML patients, other cellular models, and two relevant mouse models of the disease.
Further analyses to pinpoint the underlying mechanisms of this increased efficacy showed, to the researchers’ surprise, that “like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway,” Adams said.
Notably, BRD4 was found to suppress the activity of p53 target genes in AML, even in the presence of p53.
“Displacement of BRD4 by BET inhibition relieves this repression, leaving p53 free to activate its [anti-cancer] targets, thereby accounting for the enhanced killing of AML by combined MDM2 and BET inhibition,” the researchers wrote.
Adams noted that “between the two [therapies], you end up with a ‘double whammy’ effect that fully unleashes the anti-cancer activity of p53.”
These preclinical findings support these two agents being tested as a combination therapy in AML patients with a normal TP53 gene. They also highlighted the previously unknown p53-related potential of BRD4 suppression in treating AML.
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