Development of novel combination therapies for therapy resistant triple negative breast cancer utilising nanocarriers and repurposed drugs

Triple negative breast cancer is a highly diverse and treatment-resistant type of breast cancer which is very hard to target specifically as it lacks the three receptors (oestrogen, progesterone and human growth factor-2) that are often targeted in treatment. Therefore, this cancer type has a high recurrence and death rate. Additionally, the treatments which are available are extremely expensive and hence unaffordable in many parts of the world.

Therefore, the aim of this project is to develop novel combinations of repurposed and/or common therapies (chemotherapy and radiotherapy) to improve the efficacy of treatment and reduce resistance and tumour recurrence, whilst remaining low cost. We also aim to investigate the use of nanocarriers, such as liposomes, to deliver treatments specifically into tumour cells to discern if this can overcome treatment toxicity, improve tumour penetration to further increase efficacy, and again prevent treatment resistance.

Throughout this research we will utilise 2D analysis (clonogenic and scratch assay) to investigate the initial efficacy of the therapies, 3D analysis (spheroid models) to evaluate the treatment effectiveness against more advances models of tumours with features like the tumour microenvironment, and finally in vivo xenograft models, to investigate the efficacy of treatments in live animals, which will allow us to see if the therapies are effected by things like the immune system and gain a better insight into whether they are likely to work in humans. Mechanistic analysis using comet (DNA damage), apoptosis/ferroptosis and glutathione assaying and cell-cycle analysis by flow cytometry will also be carried out to provide a deeper understanding of the mechanisms by which the drugs alone and by their combined applications exhibit their anticancer effects.