Researchers at The University of Texas MD Anderson Cancer Center announced on July 13 that an investigational epigenetic therapy, NTX-301, remained effective in treatment-resistant acute myeloid leukemia by activating the Hippo pathway, a tumor-suppressing mechanism associated with cancer growth and drug resistance.
In preclinical models, NTX-301—a hypomethylating agent—demonstrated greater effectiveness than standard hypomethylating therapies and maintained anti-leukemia activity in cases of therapy-resistant and TP53-mutant acute myeloid leukemia. Researchers reported that the therapy activated the Hippo pathway through targeted epigenetic changes, revealing a previously unrecognized mechanism that may contribute to its anti-leukemia effects.
The findings indicate a potential new strategy for patients whose disease relapses after frontline therapy, including those with TP53 mutations, which represent one of the highest risk forms of acute myeloid leukemia. The study was led by Michael Andreeff, M.D., Ph.D., and Bing Z. Carter, Ph.D., both professors of Leukemia at MD Anderson Cancer Center. Their research was published in Clinical Cancer Research.
For many patients with acute myeloid leukemia, initial treatment with a combination of hypomethylating agents and venetoclax is often successful; however, resistance and relapse remain common challenges. This issue is particularly significant among patients with mutations in the TP53 gene—a gene responsible for helping cells respond to damage and preventing uncontrolled growth—because mutated TP53 can make leukemia cells more resistant to therapy.
NTX-301 was evaluated across several preclinical models of treatment-resistant acute myeloid leukemia—including patient-derived xenograft models—and consistently reduced survival of leukemia cells more effectively than azacitidine. Notably, NTX-301 remained active against cells already resistant to both hypomethylating therapies and venetoclax as well as against TP53-mutant models. When combined with venetoclax in resistant samples, NTX-301 produced stronger anti-leukemia effects than either drug alone; this effect extended to both blasts and stem/progenitor cells believed to drive disease persistence.
Bing Z. Carter said, "An encouraging aspect of this study is that it identified both a potential therapeutic opportunity and a biological explanation for why it may be effective. The results provide a rationale for continued clinical development and suggest that targeting Hippo signaling may help address treatment resistance in AML." Additional studies are needed to determine if these results will translate into clinical benefit for patients.
