Scrutinizing selective Aurora Kinase A inhibition as a novel entry point for synthetic lethality in neuroblastoma

01 November 2021 → 31 October 2025
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Cancer biology
    • Non-clinical studies
    • Medicinal chemistry
    • Cancer therapy
    • Pediatrics
Neuroblastoma Aurora Kinase A Synthetic Lethality
Project description

Neuroblastoma is the most common extra-cranial solid tumor in children. Currently, despite multi-modal therapy, survival rates remain disappointingly low and survivors often suffer from major long-term effects of intensive therapy. Aurora kinase A (AURKA) has previously been identified as a potential drug target in high-risk neuroblastoma. However, despite the promising preclinical data for first generation inhibitors including alisertib, barasertib and tozasertib, these pan-Aurora kinase targeting compounds did not make it successfully to the clinic due to toxicities resulting from additional AURKB/C inhibition. Recently, a highly selective AURKA inhibitor, LY3295668, which potently inhibits proliferation in a broad panel of cancer cell lines, was shown to induce apoptosis and to be highly effective in xenograft and PDX pre-clinical tumor models. These successes have prompted the selection of LY3295668 for phase I clinical trials in high-risk relapsed/refractory neuroblastomas. Single agent therapeutic strategies however often result in therapy resistance. In this project, I will exploit selective AURKA inhibition as a novel entry point for synthetic lethality in neuroblastoma through in vitro CRISPR and drug screening. Finally, I will execute for the first time a pre-clinical evaluation of AURKA-degrading PROTACs.