Synthetic rocaglates as promising therapeutic agents for aggressive hematological malignancies

项目总结/摘要 尽管在治疗开发方面取得了重大进展，但大部分血液恶性肿瘤， 尤其是攻击型的，仍然是不治之症。因此，迫切需要开发 侵袭性恶性血液病的新治疗策略。Rocaglate是一种新型RNA- 序列选择性界面抑制剂，其结合由RNA解旋酶eIF 4A和 靶mRNA的5 'UTR中的多嘌呤序列。这种结合阻止了43 S核糖体扫描， mRNA的翻译。这种独特的作用模式赋予了几个优势，rocaglate比其他 化疗剂。首先，它决定了rocaglate的高效率作用于功能 eIF 4A而不是耗尽它们。事实上，eIF 4A表达的升高增加了罗卡酯的疗效。 行动上其次，基于突变的耐药性不太可能发展，因为罗卡酯靶向两个 eIF 4A 1和eIF 4A 2以及一种同种型上的突变不能消除由eIF 4A 1和eIF 4A 2介导的rocaglate功能。 其他同种型。第三，也是最重要的是，这种独特的作用模式使rocaglate能够优先 抑制许多具有复杂5 'UTR的关键癌蛋白的mRNA翻译（选择性和多 瞄准）。我们已经证明，多种关键的癌蛋白，特别是细胞周期调节因子，以及 由于转录因子通常被认为是“不可药物化的”蛋白质， 在侵袭性B细胞淋巴瘤中被罗卡酯治疗抑制。一个可能的原因是， 癌基因具有复杂的5 'UTR，确保在正常条件下严格调节其翻译， 使他们对罗卡酯治疗非常敏感此外，癌细胞依赖性癌基因是 为了维持癌细胞代谢的增加和不受控制的肿瘤， 生长;因此，对这些癌基因上瘾的癌细胞将更容易受到罗卡酸介导的抑制。 翻译抑制比正常细胞（合成致死性）。因此，我们假设罗卡酯是一种 通过直接靶向治疗侵袭性血液恶性肿瘤的有前景的有效治疗剂 主动翻译的疾病特异性驱动癌基因的翻译起始。在这份提案中，我们将首先 通过探讨罗卡酯在不同类型肿瘤中的优先作用靶点， 血液恶性肿瘤，并确定对罗卡酯最敏感的血液癌症类型 治疗然后，我们将测试一种新开发的合成罗卡酸盐的疗效和毒性， eFT 226，在侵袭性血液恶性肿瘤的多个临床前患者来源的异种移植物模型中。

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.