Targeting MYC-driven hepatocellular carcinoma via Aurora-A ligands

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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.