Scientists have developed a new strategy against acute myeloid leukemia (AML) that pushes cancer cells to keep working even after their energy supply has been disrupted, causing them to die from metabolic stress. The study, published in the journal Molecular Cancer, reports promising results from laboratory and animal experiments.
The approach combines a newly designed molecule, called AcTor, with the existing anti-cancer drug ixazomib. In human cells and mice, the combination showed a powerful effect against AML, including forms of the disease carrying mutations in the TP53 gene that are particularly difficult to treat.
“It’s a completely new method and does not affect healthy blood cells,” said Leif A. Eriksson, PhD, professor of chemistry and molecular biology at the University of Gothenburg. “Furthermore, our studies in mice show that drug resistance is avoided, which can otherwise happen.”
AML is an aggressive blood cancer associated with outcomes, especially in older adults, with five-year survival rates of less than five percent among patients over 60. Mutations in TP53 make the cancer more aggressive, shortening overall survival to about six months. While these mutations are found in fewer than 10% of newly diagnosed cases, their frequency rises to around 40% in relapsed AML, where treatment options are limited. Cancers with these mutations can also become resistant to standard treatment, creating an urgent need for new therapeutic approaches.
Eriksson and colleagues sought to target mTOR, a protein that acts as a control center to determine whether the cell should build the components needed to grow or slow down until the conditions are right. AcTor was designed to inhibit TSC2, which controls the activation of the mTOR pathway, thus keeping the cell in an active growth state even when the cell’s energy supply is compromised. This vulnerability was exploited by combining AcTor with ixazomib, a standard treatment that disrupts mitochondrial energy production.
As a result, the cancer cell is being encouraged to press the accelerator while its energy system is being forced to hit the brakes. Unable to meet the energy demands, the leukemia cells “burn out” and die from stress.
Across multiple AML cell lines, AcTor increased the effects of ixazomib by 15-fold regardless of TP53 mutation status, while experiments in mice showed improved survival and sustained potency after relapse. Importantly, the treatment also eliminated leukemic stem cells, a small population of cancer cells that can survive therapy and contribute to relapse.
“We also observed that our treatment triggered the release of a protein (ADM2), which could therefore serve as a biomarker for the treatment’s response,” said Eriksson. “This could guide future translational and clinical studies.”
Although further studies will be needed before clinical trials in people can begin, the strategy could eventually offer a new treatment option for patients with relapsed or refractory AML, particularly those with TP53-mutated disease, who currently face some of the poorest outcomes in leukemia.
“Our study is an example of the shift towards focusing research on cancer metabolism within cells, rather than relying solely on methods that damage DNA,” said Eriksson. “Drug development is very expensive, but we hope that our findings will generate sufficient interest to enable us to continue our research into a cure for this serious disease.”
