Triple negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with limited
treatment options and poor prognosis following progression after neoadjuvant chemotherapy.
Transcriptional miRNA signatures of activation of MEK and PI3K pathways are highly prevalent in
TNBC and targeted therapies (TT) to modulate both pathways are in clinical trial. The current
challenge in clinical practice is learning to use the increasing arsenal of TT to avoid tumour
resistance and unnecessary morbidity and costs. Improved understanding of the molecular basis of
acquired resistance will lead to the development of decision tools (re)-direct rational TT
combination regimens. Exosomes, bi-layered and nanometer-sized extracellular vesicles are
promising blood-based biomarkers containing miRNA signatures that are a fingerprint of the
releasing cells and their status. The aim of this project is to guide TT decision making, based on an
exosomal miRNA biomarker to evaluate early therapeutic response and acquired resistance in TNBC.
In addition we will investigate whether acquired resistance signatures reveal sensitivity to de novo
TT to eventually maintain long-term therapeutic benefit. To achieve this we will 1) develop and
characterize TT sensitive and acquired resistant TNBC cell culture models, and isolate and determine
exosomal miRNA signatures, 2) detect spiked exosomal miRNAs in human plasma, and 3) evaluate
exosomal miRNA signatures in TNBC mouse models and index patients.