Targeting MYC-driven hepatocellular carcinoma via Aurora-A ligands

通过 Aurora-A 配体靶向 MYC 驱动的肝细胞癌

• 批准号: 409494652
• 负责人: Professor Dr. Martin Eilers
• 金额: --
• 依托单位: Fachrichtung Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409494652?language=en
• 关键词: Targeting; MYC; driven; hepatocellular; carcinoma

Hepatocellular carcinoma (HCC) presents a large unmet clinical need and new treatment options for the disease are urgently needed. Deregulation of expression of the MYC proto-oncogene is a major driver of liver carcinogenesis. The project builds on our previous observations that the stability of MYC proteins in HCC depends on complex formation with the Aurora-A kinase. As consequence, ligands of Aurora-A that alter the conformation of the kinase and disrupt the Aurora-A/MYC complex lead to a strong reduction in MYC protein levels and have therapeutic efficacy in mouse models of HCC. The aim of the project is to explore how these findings can be translated into clinical practice.Specifically, the project hast three aims: First, the cellular mechanisms by which conformation-changing Aurora-A ligands reduce MYC levels and suppress tumour growth have not been resolved and we will use a series of unbiased approaches to address both questions. Second, none of the currently clinically available inhibitors has been designed to specifically disrupt the Aurora-A/MYC complex. Since inhibiting the catalytic activity of Aurora-A is likely to have significant toxicity in vivo, we aim to use a combination of structural modelling and synthesis to design new ligands that disrupt the complex with high efficacy. These ligands and their biological effects will be thoroughly characterized. Third, we aim to use large-scale profiling to identify biomarkers that reliably indicate which tumours depend on the Aurora-A/MYC complex for growth.

肝细胞癌(肝细胞癌)是一个巨大的未得到满足的临床需求，迫切需要新的治疗方案。MYC原癌基因表达的失控是肝癌发生的主要驱动因素。该项目建立在我们之前观察到的肝细胞癌中MYC蛋白的稳定性取决于与Aurora-A激酶形成复合体的基础上。因此，Aurora-A的配体改变了激酶的构象，破坏了Aurora-A/MYC复合体，导致MYC蛋白水平显著降低，并对小鼠肝细胞癌模型具有治疗效果。该项目的目的是探索如何将这些发现转化为临床实践。具体地说，该项目有三个目标：第一，构象改变Aurora-A配体降低MYC水平和抑制肿瘤生长的细胞机制尚未解决，我们将使用一系列公正的方法来解决这两个问题。其次，目前临床上可用的抑制剂都不是专门为破坏Aurora-A/MYC复合体而设计的。由于抑制Aurora-A的催化活性在体内可能具有显著的毒性，我们的目标是结合结构建模和合成来设计高效破坏该络合物的新配体。这些配体及其生物效应将得到彻底的表征。第三，我们的目标是使用大规模的概况分析来识别可靠地表明哪些肿瘤依赖于Aurora-A/MYC复合体生长的生物标志物。