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Preferential stem cell targeting using proTide nucleoside analogues

About This PhD Project

Project Description

Applications are invited for a 3-year PhD studentship hosted at Brighton and Sussex Medical School on the University of Sussex Campus.
This studentship has developed from a partnership between Professor Chris Pepper, who has a long-standing interest in both cancer biology and drug development and the pharmaceutical company, Nucana plc. The project is designed to build upon preliminary data, which shows that proTide modification of some nucleoside drugs results in preferential targeting of leukaemic stem cells using an AML cell line model system. The precise mechanism(s) for this are yet to be elucidated but our data indicates increased intracellular bioavailability is likely to be a contributory factor. This may be mediated through enhanced drug uptake, reduced efflux and/or increased intracellular accumulation of the active triphosphate – these putative mechanisms will be explored as part of the project. The student will also investigate the role of tumour-associated hypoxia in promoting stem cell phenotypes and how this impacts upon responses to conventional drugs and nucleoside proTides. Finally, the student will study the potential for using rational combinations of nucleoside proTides and targeted agents as a means of eradicating cancer stem cells. We are seeking an enthusiastic and committed individual to join an expanding team of scientists at BSMS working on the microenvironment and drug targeting in CLL, DLBCL and AML. This training position will equip the successful candidate for a career in academia or the pharmaceutical industry and represents a unique opportunity to contribute to the development of a series of pre-clinical and clinical drug candidates.
Applicants for this 3-year funded PhD starting in April 2020 should possess or expect to be awarded a minimum of a First or Upper Second Class Honours degree (or equivalent) in Biochemistry, Biological Sciences or a relevant biomedical related subject. Both UK/EU and non-EU citizens can apply (home fees will be paid for UK/EU citizens; non-UK/EU citizens will be liable for the difference in fees between the rate for home (EU) students and the overseas student rate). Informal enquiries should be directed to Prof. Chris Pepper (). In order to apply please visit University of Brighton website. Please contact the BSMS Doctoral and Research Officer (), for any queries not related to the research project.

References (see example below):
1. Lapidot T, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367:645-48.
2. de Grouw EP, et al. Preferential expression of a high number of ATP binding cassette transporters in both normal and leukemic CD34+CD38- cells. Leukemia. 2006; 20(4):750-754.
3. Twohig JP, Cardus Figueras A, Andrews R, Wiede F, Cossins BC, Derrac Soria A, Lewis MJ, Townsend MJ, Millrine D, Li J, Hill DG, Uceda Fernandez J, Liu X, Szomolay B, Pepper CJ, Taylor PR, Pitzalis C, Tiganis T, Williams NM, Jones GW, Jones SA. Activation of naïve CD4(+) T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4(+) T cells. Nat Immunol. 2019 Apr;20(4):458-470. doi: 10.1038/s41590-019-0350-0. Epub 2019 Mar 19. PubMed PMID:30890796.
4. Escudero L, Cleal K, Ashelford K, Fegan C, Pepper C, Liddiard K, Baird DM. Telomere fusions associate with coding sequence and copy number alterations in CLL. Leukemia. 2019 Aug;33(8):2093-2097. doi: 10.1038/s41375-019-0423-y. Epub 2019 Feb 22. PubMed PMID: 30796307.
5. Norris K, Hillmen P, Rawstron A, Hills R, Baird DM, Fegan CD, Pepper C. Telomere length predicts for outcome to FCR chemotherapy in CLL. Leukemia. 2019 Aug;33(8):1953-1963. doi: 10.1038/s41375-019-0389-9. Epub 2019 Jan 30. PubMed PMID: 30700843.
6. Corcoran DB, Lewis T, Nahar KS, Jamshidi S, Fegan C, Pepper C, Thurston DE, Rahman KM. Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs). J Med Chem. 2019 Feb 28;62(4):2127-2139. doi: 10.1021/acs.jmedchem.8b01849. Epub 2019 Feb 13. PubMed PMID: 30688457.
7. Ngo G, Hyatt S, Grimstead J, Jones R, Hendrickson E, Pepper C, Baird D. PARP inhibition prevents escape from a telomere-driven crisis and inhibits cell immortalisation. Oncotarget. 2018 Dec 25;9(101):37549-37563. doi: 10.18632/oncotarget.26499. eCollection 2018 Dec 25. PubMed PMID: 30680069; PubMed Central PMCID: PMC6331021.

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