Synthetic rocaglates as promising therapeutic agents for aggressive hematological malignancies

合成罗卡格拉酯作为治疗侵袭性血液恶性肿瘤的有前景的药物

• 批准号: 10199455
• 负责人: Kai Fu
• 金额: $ 24.71万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199455
• 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; Prognosis; 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; first-in-human; in vivo; inhibitor/antagonist; interfacial; leukemia; leukemia/lymphoma; novel; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; prevent; response; ribosome profiling; small molecule inhibitor; success; targeted treatment; therapeutic evaluation; therapy development; transcription factor; transcriptome sequencing; 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.

项目摘要/摘要 尽管在治疗发展方面取得了重大进展，但很大一部分血液学恶性肿瘤，但 尤其是侵略性类型仍然无法治愈。因此，紧急未满足的开发需求 攻击性血液系统恶性肿瘤的新型治疗策略。 Rocaglade是一类新型的RNA- 序列选择性界面抑制剂，与RNA解旋酶EIF4A形成的口袋结合和 靶mRNA 5'UTR中的息肉素序列。绑定可防止43S核糖体扫描和 这种独特的行动方式承认了多种优势，可以与其他相比 化学治疗剂。首先，它决定了作用在功能上的高效率 eif4as而不是耗尽它们。实际上，EIF4A表达升高提高了Rocaglate的效率 行动。其次，基于突变的耐药性不太可能发展，因为Rocaglate均具有 EIF4A1和EIF4A2，以及一种同工型上的突变，无法废除由rocaglate功能介导的 其他同工型。第三，也最重要的是，这种独特的作用方式使Rocaglate优先 抑制许多具有复杂5'UTR的临界癌蛋白的mRNA翻译（选择性和多数 定位）。我们已经证明了多种临界癌蛋白，尤其是细胞周期调节剂 由于通常被认为是“不良”蛋白的转录因子基本上是 在侵袭性B细胞淋巴瘤中被rocaglate治疗抑制。一个可能的原因是许多关键 致癌基因的5'UTR可确保在正常条件下对其翻译的严格调节， 使它们非常容易受到Rocaglate治疗的影响。此外，癌细胞依赖性癌基因是 通常会主动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，这些癌基因的癌细胞更容易受到介导的 翻译抑制比正常细胞（合成致死性）。因此，我们假设Rocaglate是 通过直接靶向攻击性血液学恶性肿瘤的有前途和潜在的治疗剂 主动翻译的特异性驱动器癌基因的翻译启动。在此提案中，我们将首先 通过探测各种类型的Rocaglate优惠目标，剖析rocaglate的抗癌机制 血液学恶性肿瘤并确定最敏感的血液学癌症类型以rocaglate 治疗。然后，我们将测试新开发的合成rocaglate的治疗效率和毒性， EFT226，在多个临床前患者衍生的异种移植模型中，具有攻击性血液系统恶性肿瘤模型。