New epigenetic agent shows promise against resistant AML

Clinical takeaway: NTX-301 demonstrated greater preclinical anti-leukemia activity than azacitidine, remained active in venetoclax-resistant and TP53-mutant AML models, and further enhanced responses when combined with venetoclax, supporting continued clinical development in high-risk AML.

Treatment options remain limited after relapse on hypomethylating agent–venetoclax therapy, particularly for patients with TP53-mutant AML. These findings identify a potential new therapeutic strategy that could address multiple mechanisms of treatment resistance.

A next-generation hypomethylating agent, NTX-301, produced stronger anti-leukemia activity than the current standard hypomethylating agent azacitidine across multiple preclinical models of acute myeloid leukemia (AML), including patient-derived xenograft models with acquired treatment resistance. The investigational therapy retained activity in leukemia that had become resistant to both hypomethylating therapy and venetoclax and also showed efficacy in TP53-mutant AML, one of the most difficult AML subtypes to treat.

When combined with venetoclax, NTX-301 generated greater anti-leukemia effects than either agent alone and reduced not only leukemia blasts but also leukemia stem and progenitor cells, which are thought to drive disease persistence and relapse.

Mechanistic analyses suggested NTX-301 acts differently from existing hypomethylating agents by selectively reprogramming DNA methylation and activating the Hippo tumor-suppressor pathway. This increased expression of key Hippo pathway genes while suppressing YAP, a protein associated with leukemia cell survival, stemness, and drug resistance. The findings identify Hippo pathway activation as a previously unrecognized mechanism that may help explain the drug's activity in resistant disease.

"Leukemia cells are remarkably adaptable and often find new pathways to survive after treatment," said senior author Michael Andreeff, MD, PhD. "These findings suggest NTX-301 may disrupt several of those survival mechanisms simultaneously while reactivating pathways that normally restrain cell growth."

Although the findings are limited to preclinical studies, they provide a biologic rationale for clinical evaluation of NTX-301, particularly in patients with relapsed AML, venetoclax-resistant disease, or TP53 mutations.

Source: Carter BZ, et al. (2026 July 13) Clin Cancer Res. The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML