LIMR Cancer: Repurposing drugs as new treatments for breast cancer

Summary

Breast cancer (BC) is the most common cancer, with over 1 million new cases diagnosed worldwide each year. For some types of BC, hormonal treatments have been very effective but one particular BC subtype, triple negative breast cancer (TNBC), is highly aggressive and lacks a targeted therapy. New approaches are therefore desperately needed.

Recent studies in glioblastoma and melanoma have identified a new class of drugs offering potential as cancer therapeutics. These drugs have been developed for treatment of Alzheimer’s disease and inhibit the activity of the aspartic acid protease BACE1. However, high expression of BACE1 is linked to poor prognosis in TNBC and so BACE1 inhibitors are also promising candidates for treating TNBC.

BACE1 functions to cleave membrane proteins leading to changes in function. This can have dramatic effects on a diverse range of signaling pathways and responses. Given the broad actions of BACE1, changes to the tumour, immune and endothelial cell secretome following BACE1 knockdown/inhibition using state-of-the-art mass spectrometry-based proteomics will be a primary aim of the project to provide focus. Following on from this, endpoint assays measuring effects of BACE1 on hallmarks of cancer (metabolic reprofiling, growth, migration, motility, invasion) and subsequent modulation of the efficacy of chemotherapy will be a particular focus.

Previous reports suggest that BACE1 can modulate tumour cell growth (1). In support of this, our recent work suggests that BACE1 plays an important role in metabolic reprogramming (2), immune cell recruitment, and therefore tumour immunosurveillance. Additionally, BACE1 is critical for endothelial cell function (3) – and therefore implicated in vascularisation of tumours in vivo.

This project will therefore fully characterize the role of BACE1 in breast:endothelial cell, and breast:immune cell crosstalk using BACE1 inhibitors and siRNA against BACE1 using 2D and 3D co-culture models in order to closely mimic tumour micro-environment. Key findings will also be validated using isolated cells and tissues from BACE1 knockout mice, in vivomodels of cancer and patient derived cells and tissues.

The outcomes from this project could have huge potential for improving TNBC treatment through ‘drug-repurposing’.

Training will be provided in all aspects, and so no specific previous experience is required. The project will use a range of bioinformatic, cell and molecular biology techniques to achieve the aims outlined above. This includes training in 2D and 3D TNBC coculture models; drug treatments; plasmid and siRNA transfection; mass spectrometry-based proteomics; metabolic profiling; cell fate assays; flow cytometry; immunoblotting and immunofluorescent microscopy. These broad skills provide a solid basis to pursue a career in most biology fields but the appointed student will develop strong background knowledge and specific expertise that is particularly relevant to developing a research career in cancer biology.

This project is part of the International PhD Academy: Medical Research.

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.