Application and development of single cell techniques to understand drug resistance in multiple myeloma

Multiple myeloma (MM) is a cancer of plasma cells, it has the second highest incidence of haematological malignancies, accounting for 2% of all cancers. There are approximately 3000 deaths every year in the UK due to MM. Most MM patients relapse and become resistant to drugs they previously have been treated with- often patients will receive every available MM drug during their disease course. There are three main types of drug used to treat MM: proteasome inhibitors, immunomodulatory drugs and corticosteroids. The aim of the project is to explore tumour cell resistance to MM drugs, specifically proteasome inhibitors, using single cell techniques. This research could provide insight into the tumour cell resistance mechanism, this would then be considered in treatment regimens and in future drug development, potentially extending the duration an MM drug is effective and prolonging patient survival. Model MM cell lines (such as AMO-1) will be used, in addition to patient material. The aim is to use consecutive bone marrow samples from the same individual, whilst the patient is treatment-naïve, during proteasome inhibitor treatment and after they have become resistant, to explore cell changes. Experiments will be conducted to understand epigenomic and transcriptomic changes during resistance development and identify possible targets, with the aim to potentially revert drug resistance. Immune cells and bone marrow will be investigated since the tumour-microenvironment interactions are vital for development of drug resistance. RNA-Sequencing will be performed to explore differential gene expression. Experimental techniques will be implemented, alongside computational tools, to analyse the large volumes of data produced from sequencing data.
This project falls within the EPSRC 'Biological Informatics' research area and incorporates topics from biomedical sciences and bioinformatics. Resources will be drawn from MM centres here in Oxford, obtaining cell samples from clinicians. The project has been REC approved and ethical consents are in place. The project will be in close collaboration with computational biologists and biochemists. GSK is a leading pharmaceutical company in immune-oncology, and interactions are scheduled to involve regular meetings and also research stays.