Project Summary/Abstract Despite the significant advances in therapy development, a large proportion of hematological malignancies, especially the aggressive types remain incurable. Hence, there is an urgent unmet need for the development of novel treatment strategies for aggressive hematological malignancies. Rocaglate is a novel class of RNA- sequence-selective interfacial inhibitor that binds to the pocket formed by the RNA helicase eIF4A and the polypurine sequences in the 5’UTR of target mRNA. The binding prevents the 43S ribosome scanning and thus the mRNA translation. This unique mode of action confers several advantages to rocaglate over other chemotherapeutic agents. First, it determines the high efficiency of rocaglate which acts on the functioning eIF4As rather than depleting them. In fact, elevated eIF4A expression increased the efficacy of rocaglate action. Second, mutation-based drug resistance is less likely to develop because rocaglate targets both eIF4A1 and eIF4A2, and the mutations on one isoform, is unable to abolish rocaglate function mediated by the other isoform. Third and also most importantly, this unique mode of action enables rocaglate to preferentially inhibit mRNA translation of many critical oncoproteins possessing complex 5’UTR (selectivity and multi- targeting). We have demonstrated that multiple critical oncoproteins, especially the cell cycle regulators as well as the transcription factors which are usually considered as “undruggable” proteins, were substantially repressed by rocaglate treatment in aggressive B-cell lymphomas. One possible reason is that many critical oncogenes have complex 5’UTR ensuring the tight regulation of their translation in normal conditions, which makes them highly susceptible to rocaglate treatment. Moreover, cancer cell dependent oncogenes are commonly actively translated in order to sustain the increased cancer cell metabolism and uncontrolled tumor growth; and thus cancer cells addicting to these oncogenes would be more vulnerable to rocaglate mediated translation inhibition than normal cells (synthetic lethality). We therefore hypothesize that rocaglate is a promising and potent therapeutic agent for aggressive hematological malignancies through directly targeting the translation initiation of actively translated disease-specific driver oncogenes. In this proposal, we will first dissect the anti-cancer mechanism of rocaglate by probing rocaglate preferential targets in various type of hematological malignancies and identify the most sensitive types of hematological cancers to rocaglate treatment. Then, we will test the therapeutic efficacy and toxicity of a newly developed synthetic rocaglate, eFT226, in multiple preclinical patient derived xenograft models of aggressive hematological malignancies.