Targeted inhibition of mRNA translation initiation factors as a novel therapeutic strategy for mature B-cell neoplasms.

Cancer development is frequently associated with dysregulation of mRNA translation to enhance both increased global protein synthesis and translation of specific mRNAs encoding oncoproteins. Thus, targeted inhibition of mRNA translation is viewed as a promising new approach for cancer therapy. In this article we review current progress in investigating dysregulation of mRNA translation initiation in mature B-cell neoplasms, focusing on chronic lymphocytic leukemia, follicular lymphoma and diffuse large B-cell lymphoma. We discuss mechanisms and regulation of mRNA translation, potential pathways by which genetic alterations and the tumor microenvironment alters mRNA translation in malignant B cells, preclinical evaluation of drugs targeted against specific eukaryotic initiation factors and current progress towards clinical development. Overall, inhibition of mRNA translation initiation factors is an exciting and promising area for development of novel targeted anti-tumor drugs.

Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Antitumor Activity.

Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors.Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors.Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100× relative dosing, leading to significant activity against lymphoma xenografts.Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy. Clin Cancer Res; 24(17); 4256-70. ©2018 AACR.