Project: We are seeking enthusiastic and talented candidates for an iCASE PhD project in collaboration with AstraZeneca to investigate drug uptake in cells. Understanding cellular uptake and target engagement of drugs are of critical importance to determine whether intracellular drug concentration in cells is sufficient to hit their target. In this project, we will develop microfluidic instrumentation to directly measure drug uptake in metastatic cancer cells and assess their response.
Current approaches allow us to capture the rich heterogeneity in response from a population of cancer cells to drugs; observing differentially responding cells (changes in protein expression) and with the presumption that the drug is showing productive uptake in these cells. But this is problematic if cellular activity is weak or absent. In non-responding cells, is target engagement limited or altered due to emerging resistance mechanisms? Are there differences in penetration or efflux mechanisms (enhanced in certain cells) that would lower the effective in-cell drug concentration in some subpopulations? The answers are critically important in guiding, i) immediate clinical decisions toward likely effective alternatives, and ii) the longer-term chemical design of drug candidates. Should drug design focus on stronger potency or enhancing cellular compound penetration? Is the drug being lost into other cell types? Capitalising on the ability to isolate rare cells, we will develop our microfluidic platforms to measure in-cell drug concentrations, achieved by hyphenation with mass spectrometry (MS) to understand these responses in the context of in-cell drug and metabolite concentrations. MS is rapidly becoming a powerful approach and playing a prominent role in single-cell analysis due to its high sensitivity, and information-rich, label-free readouts
The outputs of the project will support therapeutic and biomarker discovery. Such a methodology could be deployed early in hit discovery to help predict and understand differences in biochemical and in vivo cellular activity and ultimately influence compound progression decisions. This project would suit candidates with a strong background in analytical chemistry and microfluidic engineering, who have an interest in the translational potential of their work. Applications from those who have significant laboratory-based experience are encouraged. As part of this project, we will work closely with the Analytical and Structural Chemistry (ASC) group at AstraZeneca’s Cambridge laboratories, with a placement of up to 3 months. The project would, therefore, suit candidates interested in spending part of their research time in an industrial setting.
Supervisory Team: Dr Ali Salehi-Reyhani (link) a Lecturer in Convergence in the Dept. Surgery & Cancer at Imperial College London, with a background in physics and analytical chemistry. He is a UKRI Innovation fellow and holds a lectureship from the Community of Analytical Measurement Science UK. He leads the Analytical Systems Research group, working to improve health through the development of novel instrumentation and technological innovation in microfluidic engineering and miniaturised sensors. Prof. Charles Coombes (link) is a Professor of Medical Oncology and an Hon. Consultant Medical Oncologist at the Imperial College Healthcare Trust. He is the Chairman of The International Collaborative Cancer Group. His research focuses on developing novel methods for predicting response to endocrine therapy in breast cancer and also carrying out research aimed at understanding the mechanisms of resistance to endocrine therapy and the development of novel anti-cancer drugs.
Programme: iCASE (Industrial Cooperative Awards in Science & Technology) projects provide outstanding students access to training, facilities and expertise not available in an academic setting alone. Students benefit from a diversity of experimental approaches with an applied / translational dimension. Students have an opportunity to develop a range of valuable skills and significantly enhance their future employability; many will become research leaders of the future. The programme embodies a “blue-skies” approach to research with an analytical and modelling focus. The Faculty of Medicine (link) is exceptionally well-equipped to support pioneering research with state-of-the-art analytical instrumentation hosting the MRC-NIHR National Phenome Centre (link), with access to the Agilent Measurement Suite (link) and the Advanced Hackspace for prototyping (link).
Application: Applications are invited for a 4-year EPSRC iCASE studentship within the Division of Cancer to start on the 1st October 2021. Candidates are strongly advised to contact the supervisors prior to applying. To apply - 1) Send a full CV, examination transcripts for major degrees (predicted grades for studies which are still in progress) and a covering letter with contact details of two referees (at least one academic) to Dr Ali Salehi-Reyhani (ali.salehi-reyhani at imperial.ac.uk). 2) Short-listed candidates will be informed by email and invited for interview. The Studentship is funded for 4 years and covers the full cost of Home tuition fees. Income tax is not payable on the stipend. This scheme only covers funding for Home students. Applicants from other countries can apply but would need to cover international student fees from other sources. Details of the iCASE scheme may be found here.
Candidate profile: You must fulfil all Imperial College PhD entry requirements (link). Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a physical sciences subject (Chemistry, Physics, Engineering) and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject. This project is ideal for a talented, enthusiastic and driven candidate who is excited about developing novel methods and analytical instrumentation. You will collaborate and coordinate research with world-leading engineers, analytical chemists and clinicians which requires a highly multidisciplinary approach.