Brain metastases are a major cause of cancer-related mortality in breast, lung, and melanoma. Survival rarely exceeds one year, and there are no reliable biomarkers to identify patients at risk or to guide use of brain-penetrant treatments.
Our recent studies uncovered a conserved proliferative transcriptional program, active in primary tumours and re-engaged during brain colonisation. This program is coordinated by Aurora kinase A (AURKA) and FOXM1, two mitotic regulators that cooperate to sustain cell-cycle and DNA-repair transcription. The central hypothesis is that central AURKA-FOXM1 drives metastatic outgrowth in the brain microenvironment.
We will:
Functionally validate the conserved proliferative module (CM4) in brain metastasis models and define its regulatory architecture
Determine how disruption of this axis-through genetic silencing or the brain-penetrant AURKA inhibitor alisertib-affects proliferation and drug response in organoid, organotypic, and in vivo models.
Develop a compact tissue IHC biomarker panel and plasma cfRNA reporting AURKA-FOXM1 axis activity for early detection and patient stratification.
Although discovered in breast cancer, this proliferative signature is also enriched in other brain metastases (including lung cancer), indicating a conserved mechanism across tumour types.
By integrating mechanistic discovery with therapeutic testing and biomarker development, this project will provide actionable insight into metastatic progression, deliver pre-clinical validation of a druggable pathway, and establish translational tools for earlier diagnosis and improved treatment of patients with cancers prone to brain spread.