Identifying New Drug Targets to Treat Breast Cancer Brain Metastasis
Breast cancer brain metastasis (BrM) is indicative of poor prognosis, with a short median survival time and limited disease management strategies. Current treatment options are restricted to surgical resection, radiation therapy and limited targeted therapies. Therefore, there is an urgent need to uncover alterations responsible for BrM and to define novel effective therapeutic targets.
RNA-sequencing (RNA-Seq) was performed to analyse gene expression differences between patient-matched breast tumours and their associated resected BrM. Importantly, common transcriptional differences in breast cancer specific genes were observed, particularly BrM–acquired aberrant enrichment in multiple receptor tyrosine kinase (RTK) driven signalling pathways. The most notable recurrent alterations were expression gains in RET and HER2. Hence, given the observed enriched kinase landscape these alterations were investigated as clinically actionable therapeutic targets in BrM.
To evaluate the effect of RET and HER2 inhibition in a preclinical setting, the efficacy of two FDA-approved agents were examined; a RET inhibitor, cabozantinib, and a pan-HER inhibitor, afatinib. Being small molecule tyrosine kinase inhibitors (TKIs), both drugs have the potential of crossing the blood brain barrier (BBB). In vitro, both agents demonstrated a significant effect on the cellular viability and migratory capacity of brain-metastasising cell lines and primary cells derived from a patient brain metastasis tumour. Significant anti-tumour activity was also shown for anti-HER2 and anti-RET therapies in unique patient derived ex vivo and patient-derived xenograft (PDX) models developed from patients undergoing BrM resection.
This study demonstrates profound and recurrent transcriptional remodelling events in BrM, which is critical to understanding the pathobiology of BrM. Furthermore, this work supports comprehensive profiling of metastasis as a compelling and underutilised tool to inform clinical care and reveal novel targeted treatment paradigms. Given the remarkably high recurrence rates of specific targetable alterations, further clinical investigations of recurrent aberrations are in demand, especially considering some are readily druggable.
First SupervisorProf. Leonie Young
Second SupervisorDr. Damir Vareslija
- Master of Science (MSc): Research