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Exosomes in oncolytic virotherapy


Project Description

THE PROJECT
Oncolytic viruses promise new opportunities for targeted cancer therapy, but spread of viruses through solid tumour masses is often limited. Sometimes this is thought to reflect stress responses within the tumour tissue. This D.Phil. project will explore the possibility of using exosomes produced from virus-infected cells to ‘condition’ other cells within the tumour microenvironment. It will focus initially on characterising exosomes produced from virus infected tumour cells to determine which virus components are packaged into exosomes most efficiently. The work will use type 5 adenovirus because most tools are available for that agent aiming to engineer viruses to promote spread of chosen proteins to nearby cells. We will also assess hypothesis that microRNA are incorporated randomly into exosomes, and that the highest expression can lead to most efficient packaging. Successful development of this exosome-targeting system would enable design of oncolytic viruses that are capable of preparing nearby cells for virus infection, and preventing stress-related inhibition of spread.

Main outputs of the studentship: Characterise mechanisms for viral agents to exploit natural (or virus-induced) exosome pathways to distribute effector molecules or therapeutics around the tumour microenvironment. In this way we aim to condition uninfected cells to encourage better virus spread under conditions of cellular stress/hypoxia, and to allow therapeutic proteins to penetrate beyond the limits of virus spread and thereby increase their effectiveness.

THE TRAINING
The student would join a dynamic research group (approx. 15 personnel) with a good friendly and engaging culture. There will be extensive molecular biological and virological training, coupled with strong immunological focus. We encourage applications from ambitious students with an interest in understanding molecular mechanisms and exploiting them for therapeutic benefit.

PUBLICATIONS
Freedman, J., Muntzer, A., Duffy, M., Lei, J., Bryant, R., Verrill, C., Lambert, A., Miller, P., Seymour, L. and Fisher, K., Multimodal oncolytic virus encoding a bispecific antibody that retargets endogenous T cells to attack tumour-associated fibroblasts, thereby combining direct cytotoxicity with active reversal of local immunosuppression, Cancer Research (published online November 18th 2018) DOI: 10.1158/0008-5472.CAN-18-1750

Dyer, A., Schoeps, B., Frost, S. Jakeman, P., Scott, E., Freedman, J. Seymour, L.W., Antagonism of glycolysis and reductive carboxylation of glutamine potentiates activity of oncolytic adenoviruses in cancer cells, Cancer Research published online November 28th DOI: 10.1158/0008-5472.CAN-18-1326

Lei J, Jacobus EJ, Taverner WK, Fisher KD, Hemmi S, West K, Slater L, Lilley F, Brown A, Champion B, Duffy MR, Seymour LW. Expression of human CD46 and trans-complementation by murine adenovirus 1 fails to allow productive infection by a group B oncolytic adenovirus in murine cancer cells. J Immunother Cancer. 2018 Jun 13;6(1):55

Funding Notes

All complete applications received by 12 noon (UK time) on Friday 10 January 2020 will automatically be considered for all relevant competitive University and funding opportunities, including the Clarendon Fund, Medical Research Council funding, and various College funds. Please refer to the Funding and Costs webpage (View Website) for this course for further details relating to funded scholarships and divisional funding opportunities.

Funded studentships are highly competitive and are awarded to the highest ranked applicant(s) based on the advertised entry requirements for each programme of study.

References

Whilst you must register three referees, the department may start the assessment of your application if two of the three references are submitted by the course deadline and your application is otherwise complete. Please note that you may still be required to ensure your third referee supplies a reference for consideration.

Academic references are strongly encouraged, though you may use up to one professional reference provided that it is relevant to the course.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

Research output data provided by the Research Excellence Framework (REF)

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