Synthetic rocaglates as promising therapeutic agents for aggressive hematological malignancies

合成罗卡格拉酯作为侵袭性血液恶性肿瘤的有前途的治疗剂

• 批准号: 10347374
• 负责人: Kai Fu
• 金额: $ 16.81万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347374
• 关键词: 5' Untranslated Regions; Active Sites; Adopted; Affect; Aglaia; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; Binding; Biological Assay; Biological Markers; Cell Cycle; Cells; Clinical Management; Clinical Trials; Collaborations; Complex; DNA Damage; Development; Disease; Drug resistance; Effectiveness; Ensure; Future; Genes; Genetic Translation; Goals; Hematologic Neoplasms; Investigational Drugs; Lymphoma; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Methods; Molecular; Multiple Myeloma; Mutation; Natural Products; Newly Diagnosed; Normal Cell; Oncogenes; Oncoproteins; Pathogenesis; Patients; Pharmaceutical Preparations; Plants; Pre-Clinical Model; Protein Isoforms; Proteins; Proteomics; RNA Helicase; RNA Sequences; Refractory; Regimen; Regulation; Relapse; Reporting; Research Personnel; Resistance development; Ribosomes; Scanning; Solid Neoplasm; Structure of germinal center of lymph node; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Translating; Translation Initiation; Translations; Treatment Efficacy; Treatment-related toxicity; Tumor Suppression; anti-cancer; base; c-myc Genes; cancer cell; cancer therapy; chemical synthesis; chemotherapeutic agent; cohort; disease prognosis; first-in-human; in vivo; inhibitor; interfacial; leukemia; leukemia/lymphoma; novel; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; prevent; ribosome profiling; small molecule inhibitor; success; targeted treatment; therapeutic evaluation; therapy development; transcription factor; transcriptome sequencing; treatment response; treatment strategy; tumor growth; tumor metabolism

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.

项目概要/摘要 尽管治疗开发取得了重大进展，但很大一部分血液恶性肿瘤 特别是侵袭性类型仍然无法治愈，因此，迫切需要开发未满足的需求。 Rocaglate 是一种新型 RNA- 治疗策略。 序列选择性界面抑制剂，与 RNA 解旋酶 eIF4A 和 目标 mRNA 5'UTR 中的多聚嘌呤序列结合可阻止 43S 核糖体扫描和 因此，这种独特的作用模式赋予了 rocaglate 优于其他药物的优势。 首先，它决定了罗卡列作用于功能的高效性。 eIF4A 表达增加而不是耗尽它们，事实上，eIF4A 表达的升高增强了罗卡格特的疗效。 其次，基于突变的耐药性不太可能发生，因为罗格列同时针对这两种药物。 eIF4A1 和 eIF4A2 以及一种亚型的突变无法消除由 rocaglate 介导的功能 第三，也是最重要的是，这种独特的作用模式使罗卡格特能够优先发挥作用。 抑制许多具有复杂 5’UTR 的关键癌蛋白的 mRNA 翻译（选择性和多端性） 我们已经证明了多种关键癌蛋白，尤其是细胞周期调节蛋白。 作为通常被认为是“不可成药”蛋白质的转录因子，基本上 侵袭性 B 细胞淋巴瘤中罗格列特治疗会抑制这种作用，一个可能的原因是许多关键因素。 癌基因具有复杂的 5'UTR，确保其翻译在正常条件下受到严格调控，这 使它们对罗格列特治疗高度敏感。此外，癌细胞依赖性癌基因。 通常积极翻译以维持增加的癌细胞代谢和不受控制的肿瘤 生长；因此对这些癌基因上瘾的癌细胞将更容易受到罗卡格特介导的影响。 因此，我们认为罗卡格特是一种比正常细胞更强的翻译抑制作用（合成致死率）。 通过直接靶向治疗侵袭性血液恶性肿瘤的有前途且有效的治疗剂 主动翻译的疾病特异性驱动癌基因的翻译启动在本提案中，我们将首先。 通过探索罗卡列在不同类型癌症中的优先靶点，剖析罗卡列的抗癌机制 血液恶性肿瘤并确定对罗格列最敏感的血液癌症类型 然后，我们将测试新开发的合成罗卡格特的治疗效果和毒性， eFT226，在多个临床前患者衍生的侵袭性血液恶性肿瘤异种移植模型中。