Understanding the role of STAT3 in therapy-resistance and metastatic progression of breast cancer

Resistance to endocrine and other therapies during metastatic progression is the major cause of mortality in breast cancer. We have previously reported that endocrine resistance can be driven by ALDH+ breast cancer stem cells (CSCs) and more recently that STAT3 is activated in these cells (Simoes et al., 2015 and 2020). We and others have reported that breast cancers resistant to the recently FDA-approved CDK4/6 inhibitors such as Palbociclib have increased numbers of CSCs and activation of STAT3 signalling, and that inflammatory and obesity-related breast cancer are driven by IL6 and leptin activating STAT3 transcriptional activity.

Our hypothesis is that targeting STAT3 would benefit breast cancer patients where CSCs are driven by the STAT3 signalling pathway, and in particular would combat therapy resistance and metastatic progression. In the Clarke lab, we have established in vitro and in vivo models of breast cancer patient-derived organoids and xenografts that metastasise to relevant organs such as lung and bone (Byrne et al., 2017, Eyre et al., 2019). The student will use these models to perform CSC assays, gene and protein expression analyses to characterise the signalling pathways targeted by SFX-01 and discover biomarkers that predict response.

The potential outcome is the definition of which breast cancers have STAT3 dependency and are sensitive to STAT3-targeted therapies. We aim to understand the mechanisms of STAT3 signalling and establish predictive biomarkers that will have translational value in precision medicine clinical trials, which the appointed student would help design during a placement in the iCASE partner company Evgen Pharma PLC, who aim to develop SFX-01 for improved breast cancer therapy.