Synthetic rocaglates as promising therapeutic agents for aggressive hematological malignancies

项目摘要/摘要 尽管在治疗开发方面取得了重大进展，但很大比例的血液系统恶性肿瘤， 尤其是攻击型仍然是不治之症。因此，发展……的迫切需要尚未得到满足。 侵袭性血液系统恶性肿瘤的新治疗策略。Rocagate是一类新的RNA- 序列选择性界面抑制物，结合到由RNA解旋酶eIF4A和 目的基因5‘端非编码区的多嘌呤序列。这种结合阻止了43S核糖体扫描和 从而实现了信使核糖核酸的翻译。这种独特的行为模式赋予了Rocagate相对于其他公司的几个优势 化疗药物。首先，它决定了岩盐的高效率，它作用于功能 EIF4A，而不是耗尽它们。事实上，eIF4A表达的升高增加了罗卡酸盐的疗效 行动。其次，基于突变的耐药性不太可能发生，因为罗格列特既针对这两种药物 EIF4A1和eIF4A2，以及一个异构体上的突变，不能取消由 其他异构体。第三，也是最重要的一点，这种独特的行动模式使Rocagate能够优先 抑制许多具有复合体5‘非编码区(选择性和多重链)的关键癌蛋白的mRNA翻译 目标)。我们已经证明了多种关键的癌蛋白，特别是细胞周期调节蛋白 因为通常被认为是“不能下药的”蛋白质的转录因子基本上 在侵袭性B细胞淋巴瘤中被罗格芬治疗抑制。一个可能的原因是许多关键的 癌基因有复杂的5‘非编码区，确保了它们在正常情况下翻译的严格调控，这 使他们对岩石酸盐治疗高度敏感。此外，癌细胞依赖的癌基因是 通常主动翻译，以维持癌细胞代谢增加和肿瘤失控 因此，对这些癌基因上瘾的癌细胞将更容易受到罗卡酸盐介导的影响。 翻译抑制比正常细胞(合成致死性)。因此，我们假设岩酸盐是一种 直接靶向治疗侵袭性血液系统恶性肿瘤的有效药物 主动翻译的疾病特异性驱动癌基因的翻译启动。在这项提案中，我们将首先 通过探索不同类型岩屑的优势靶点剖析岩屑的抗癌作用机制 血液系统恶性肿瘤，并确定对罗卡酸盐最敏感的血液系统肿瘤类型 治疗。然后，我们将测试一种新开发的合成岩酸盐的治疗效果和毒性， EFT226，在多种临床前患者衍生的侵袭性血液系统恶性肿瘤的异种移植模型中。

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.