Suitable for Honours or PhD students.
TP53 is the most frequently mutated gene, with over half of all human tumours harbouring mutation of this gene. Unlike the majority of tumour suppressor genes that are inactivated as a result of truncating mutations, the majority of TP53 mutations are missense resulting in accumulation of mutant protein and gain-of-function activity. The mutational status of p53 predicts poor outcomes, resistance to chemotherapies, and shorter overall survival in multiple types of cancer, including breast cancer (BC)), which is the focus of this project.
Over several decades considerable effort has been applied to develop drugs to target mutant p53 (mut-p53), with none in routine clinical use. In this proposal, we aim to repurpose an FDA approved drug to target mut-p53 tumours. We propose to develop clinically relevant combinatorial approaches that will yield novel therapeutic strategies to treat cancers with p53 mutations. We have compelling data that an FDA-approved drug (designated as molecule-1) used for another disease indication; can be repurposed for therapeutic targeting of mut-p53 cancers. Our data convincingly demonstrate that treatment of mut-p53 expressing cells with molecule-1 can reactivate the wild-type transcriptional activity of mut-p53.
In this project, we will optimise the anti-tumour effect of this molecule in our clinically relevant mut-p53 patient derived xenograft (PDX) models in combination with conventional chemotherapies. Additionally, we will identify other FDA-approved compounds that synergise with this molecule to further improve its efficacy in mut-p53 cancers. We will also establish the mechanism of mut-p53 reactivation by this molecule through p53 structural analysis, providing valuable insights into the actions of this drug on mut-p53, thus identifying further potential opportunities for therapeutic targeting of mut-p53 in tumour cells.