Epigenetic Therapy NTX-301 Activates Hippo Pathway to Overcome Treatment-Resistant AML
核心洞察
Investigational hypomethylating agent NTX-301 demonstrated stronger anti-leukemia activity than azacitidine across multiple preclinical models of treatment-resistant AML.
The therapy remained effective in TP53 (搜索)-mutant and venetoclax-resistant leukemia cells, and enhanced responses when combined with venetoclax against both blasts and leukemia stem cells.
Researchers identified activation of the Hippo tumor-suppressing pathway through targeted epigenetic changes as a previously unrecognized mechanism behind NTX-301's anti-leukemia effects.
An investigational next-generation epigenetic therapy has demonstrated potent anti-leukemia activity in preclinical models of treatment-resistant acute myeloid leukemia (搜索) (AML), outperforming standard hypomethylating therapy and revealing a previously unrecognized mechanism involving the Hippo tumor-suppressing pathway, researchers at The University of Texas MD Anderson Cancer Center reported.
The study, published in Clinical Cancer Research, a journal of the American Association for Cancer Research, found that NTX-301 — a hypomethylating agent — was more effective than azacitidine, a commonly used hypomethylating agent, across multiple preclinical models of treatment-resistant AML, including patient-derived xenograft (PDX) models with acquired resistance. The research was led by Michael Andreeff, M.D., Ph.D., and Bing Z. Carter, Ph.D., both professors of Leukemia at MD Anderson.
"Leukemia cells are remarkably adaptable and often find new pathways to survive after treatment," Andreeff said. "These findings suggest NTX-301 may disrupt several of those survival mechanisms simultaneously while reactivating pathways that normally restrain cell growth. That dual effect could help explain why NTX-301 remained active in some of the most therapy-resistant forms of AML."
The challenge of treatment resistance in AML
For many patients with AML, the frontline combination of hypomethylating agents and venetoclax works well initially, but resistance and relapse remain common. The challenge is particularly significant in AML with mutations in the TP53 (搜索) gene, which normally helps cells respond to damage and prevent uncontrolled growth. When that gene is mutated, leukemia cells can become resistant to therapy and more difficult to eliminate, representing one of the highest risk forms of the disease.
NTX-301 activity in resistant disease models
In the study, NTX-301 consistently reduced leukemia cell survival more effectively than azacitidine. Critically, the therapy remained active in leukemia cells that had already developed resistance to both hypomethylating therapy and venetoclax, and it showed anti-leukemia activity in TP53 (搜索)-mutant AML models.
When combined with venetoclax in resistant leukemia samples, NTX-301 produced stronger anti-leukemia effects than either treatment alone. The combination was effective not only against leukemia blasts but also against leukemia stem and progenitor cells, which are believed to contribute to disease persistence and relapse.
Hippo pathway (搜索) reactivation as a novel mechanism
To understand why NTX-301 appeared more effective than existing drugs, researchers analyzed changes in DNA methylation — a process that can switch genes on or off without altering the underlying genetic code. Unlike current hypomethylating therapies, which broadly affect DNA methylation, NTX-301 focused on a more selective set of genes and pathways, including the Hippo pathway (搜索), which functions as a natural cell growth regulator.
NTX-301 increased activity of key Hippo pathway (搜索) genes while reducing activity of YAP (搜索), a protein frequently linked to cancer cell survival, treatment resistance, and stemness. These findings suggest Hippo pathway reactivation may be an important reason the therapy remained effective in resistant leukemia models and could represent a new strategy for overcoming treatment resistance in AML.
Clinical development path forward
Additional studies are needed to determine whether these results translate to patients and to identify which populations may benefit most. The findings suggest that patients with relapsed AML, venetoclax-resistant disease, and TP53 (搜索) mutations may be important groups for future clinical evaluation.
"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," Carter said. "The results provide a rationale for continued clinical development and suggest that targeting Hippo signaling may help address treatment resistance in AML."