Lost in Translation: Inhibiting eIF4A to Treat AML

/ABSTRACT Despite advancements in acute myeloid leukemia (AML) therapies such as venetoclax plus azacitidine (ven/aza), the overall 5-year survival rate remains only 27%. Most AML patients experience relapse or refractory disease, often due to a subset of AML cells that persist through therapy–leaving few, if any, effective treatment options. There is a critical need for improved therapies that eradicate AML cells. The investigators show that AML cells highly express the eukaryotic translation initiation factor 4A (eIF4A). Through its helicase function, eIF4A selectively promotes translation of oncogenes essential for AML cell survival. AML cells are sensitive to the clinical-grade eIF4A inhibitor zotatifin, and zotatifin is synergistic with the widely used BCL-2 inhibitor venetoclax. Questions remain regarding the in vivo therapeutic window, comparison to standard of care, and biomarkers of response to zotatifin-based combination therapies. The long-term goal of this research is to accelerate the development of new molecularly targeted therapies that improve treatment outcomes for AML patients. The overall objective is to validate the eIF4A inhibitor zotatifin as a small molecule to target AML cells. The central hypothesis is that zotatifin selectively targets AML cells over healthy cells and synergizes with venetoclax by inhibiting translation of oncogenes. The rationale for the proposed research is that rigorous evaluation of zotatifin, alone and in combination therapies, is likely to accelerate its development as part of novel treatment regimens for AML patients. Guided by preliminary data and expert collaborators, the central hypothesis will be tested by pursuing three specific aims: 1) Evaluate zotatifin’s safety and selectivity for AML over healthy hematopoietic cells, 2) Compare the efficacy of zotatifin combination treatments to standard of care, and 3) Determine how eIF4A inhibition sensitizes AML cells to apoptosis. In Aim 1, the investigators will assess toxicity and compare the effect of zotatifin treatment, alone or with ven/aza, on healthy cells vs. AML cells. In Aim 2, they will compare the combination of zotatifin with ven/aza to standard-of-care regimens in patient-derived xenograft (PDX) mouse models, which together with the mouse studies in Aim 1 are essential to evaluate zotatifin’s in vivo safety, therapeutic window, and combinatorial efficacy that cannot be recapitulated in vitro. In Aim 3, they will identify the downstream targets of zotatifin that mediate cell death as potential biomarkers of response. The proposed research is innovative because it departs from the status quo by establishing translation initiation as a selectively regulated and targetable pathway in AML, providing a rigorous assessment of zotatifin as a novel therapeutic agent, and defining how it sensitizes AML cells to apoptosis. The proposed research is significant because it is expected to establish protein translation as a tractable therapeutic target in AML and generate the preclinical foundation needed to support clinical trials with zotatifin. Project Number: 1R01CA311561-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Peter van Galen | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $409,463 | Activity Code: R01 | Study Section: Advancing Therapeutics A Study Section [ATA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11341495