To understand mechanisms that mediate chemo-/radioresistance of breast cancer stem cells

Suitable for Honours or PhD students.

Precursor metastatic cells, referred to as ‘cancer stem cells’ (CSCs), play a pivotal role in metastasis and relapse in breast cancer (BC) patients. Thus, effective management of breast cancer will require new therapeutic strategies that eliminate CSCs. Nonetheless, drugs that specifically target CSCs are extremely under-developed.  We have made a novel finding that expression of a new kinase is linked to breast cancer stemness as well as radioresistance. To date, this kinase has not been studied in breast cancer.  Moreover, the signalling pathways regulated by kinase or its upstream regulators are unknown at present – not to mention in a context of radiobiology and chemotherapy. It clearly warrants further investigation. The study will establish the clinicopathological importance of identified kinase with other breast CSC markers in primary human BCs with clinical outcome data, providing clinical correlations to underlying biology and paving the way for companion diagnostic. We will study the effect of combined kinase depletion followed by IR treatment or chemotherapy on tumour recurrence in in vivo murine xenograft models in order to generate basic and preclinical data to support the development of kinase inhibitors that target cancer stem cells in women with BC. These studies will determine the role of resistant CSCs in tumour regrowth (recurrence) and how the specific eradication of these cells provides means for successful and curative approaches.  It is anticipated that our mechanistic study on this kinase in in vitro cell line models and/or in vivo xenograft models will shed light on a new signalling axis that is critical to regulating breast cancer stemness and improving current clinical radiotherapy and chemotherapy for BC patients. The long-term aim of our research is to develop more effective therapies for advanced breast cancer. The identification of therapeutically exploitable kinase that is an important mediator of CSCs function after chemo- and radiotherapy will improve the success of standard and widely used DNA damage-based chemotherapy. If the proposed mechanistic studies demonstrate a causal role for this kinase and its regulated pathways in causing disease recurrence/relapse, a unique opportunity will exist to develop a new therapy in a group of patients with poor outcome. By inhibiting this kinase, it will be possible to substantially reduce CSC levels thereby diminishing cancer recurrence.