Failure of chemotherapeutic agents to kill cancer cells is attributed to resistance mechanisms acquired by the cancer cells, often through evasion of apoptosis. A new group of drugs called BH3 mimetics target the anti-apoptotic BCL-2 family of proteins and efficiently eliminate cancer cells by initiating the intrinsic apoptotic pathway. Using these drugs along with a large panel containing hundreds of FDA-approved drugs, we intend to identify novel drug combinations/ metabolic pathways that can be exploited to improve cancer therapy.
The proposed study will begin with a high-throughput drug library screen to identify drugs that will induce apoptosis or cytostatic effects, when administered as single agents or in combination with BH3 mimetics in cancer cell lines derived from patients. Positive hits will be validated and further characterised by employing a range of techniques, including apoptosis and proliferation assays, clonogenic assays, flow cytometry, western blotting, RNA interference, confocal and electron microscopy, immunohistochemistry, spheroid and organoid tissue culture, patient-derived explant culture, tissue microarray analysis and in vivo studies involving zebrafish embryos.
The prospective student will join a highly dynamic and motivated team of researchers in the Varadarajan Lab (https://www.varadarajanlab.org) and the Liverpool Head and Neck Centre (https://www.liverpool.ac.uk/health-and-life-sciences/research-departments/liverpool-head-and-neck-centre/), which encompasses the clinical units and research groups within the University of Liverpool, Aintree University Hospital NHS Foundation Trust, The Clatterbridge Cancer Centre NHS Foundation Trust, The Walton Centre NHS Foundation Trust, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners. LHNC offers a world-class programme of translational research directed at enhancing the quality and safety of patient care.
Candidates should be self-motivated, hard-working and have an undergraduate and/or Masters degree in biology, biochemistry, pharmacy or related areas.
Please contact Dr Shankar Varadarajan via [Email Address Removed] registering your interest in the studentship, prior to applying.
We are looking for self-funded students or students who have secured funding from an independent body. The successful applicant will be expected to provide the funding for tuition fees (check University of Liverpool website), consumables fee (£15000 per annum) and living expenses during their stay in Liverpool.
(1) Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in haematological malignancies. Al-Zebeeby A., Vogler M., Milani M., Richards C., Alotibi A., Greaves G., Dyer MJS., Cohen GM. & Varadarajan S. Haematologica, Epub. doi:10.3324/haematol.2018.204701
(2) BH3-only proteins are dispensable for apoptosis induced by pharmacological inhibition of both MCL-1 and BCL-XL. Greaves G., Milani M., Butterworth M., Carter RJ., Byrne DP., Eyers PA., Luo X., Cohen GM. & Varadarajan S. Cell Death and Differentiation, Epub. doi: 10.1038/s41418-018-0183-7
(3) BH3 profiling and a toolkit of BH3-mimetic drugs predict anti-apoptotic dependence of cancer cells. Butterworth, M., Pettitt, A., Varadarajan, S. & Cohen, G. M. British Journal of Cancer, 114(6), 638-641. doi: 10.1038/bjc.2016.49