Targeting MYC-driven hepatocellular carcinoma via Aurora-A ligands

肝细胞癌（HCC）呈现出大量未满足的临床需求，迫切需要新的治疗方案。MYC原癌基因表达的失调是肝癌发生的主要驱动因素。该项目建立在我们之前的观察基础上，即HCC中MYC蛋白的稳定性取决于与Aurora-A激酶的复合物形成。因此，Aurora-A的配体改变了激酶的构象，破坏了Aurora-A/MYC复合物，导致MYC蛋白水平大幅降低，并在小鼠HCC模型中具有治疗效果。该项目的目的是探索如何将这些发现转化为临床实践。具体来说，该项目有三个目标：首先，构象改变的Aurora-A配体降低MYC水平和抑制肿瘤生长的细胞机制尚未得到解决，我们将使用一系列公正的方法来解决这两个问题。其次，目前临床可用的抑制剂中没有一种是专门用于破坏Aurora-A/MYC复合物的。由于抑制Aurora-A的催化活性可能在体内具有显著的毒性，我们的目标是采用结构建模和合成相结合的方法设计新的配体，高效地破坏该复合物。这些配体及其生物学效应将被彻底表征。第三，我们的目标是使用大规模的分析来确定生物标志物，这些生物标志物可靠地指示哪些肿瘤依赖Aurora-A/MYC复合体生长。

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.