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Validation of TRAF6/PD-L1 inhibition in pre-clinical models of multiple myeloma: implications for combinational immunotherapy


   Department of Oncology and Metabolism

  Dr A Idris, Dr Michelle Lawson  Tuesday, January 31, 2023  Self-Funded PhD Students Only

About the Project

Programmed death-ligand 1(PD-L1), a negative regulator of the immune system, is highly expressed in newly-diagnosed and relapsed multiple myeloma patients, and its expression is associated with suppressed anti-tumour immunity. Therapeutic antibodies directed at PD-L1 show promise for the treatment of difficult-to-treat cancers such as multiple myeloma, however numerous studies have shown that only a small proportion of cancer patients respond to these agents. TRAF6, a component of the pro-inflammatory and immuno-modulatory NFκB pathway, is highly expressed in multiple myeloma cells, and its genetic inhibition exerts anti-myeloma effects in vitro. We have identified a novel class of TRAF6 inhibitors that exhibited anti-tumour and anti-osteolytic properties in various mouse models of metastatic cancer, inhibited the viability of a panel of mouse and human multiple myeloma cells, suppressed multiple myeloma-induced bone cell activity, and reduced PD-L1 expression induced by immune- and bone-derived factors in human multiple myeloma cells.

This PhD programme will build on these unpublished findings, and our group previous published work on the role of TRAF/NFkB pathway in metastasis, and employ standard preclinical in vitro and in vivo models of mouse and human multiple myeloma to test if treatment with our novel TRAF6 inhibitors – alone or in combination with PD-L1 or T-cell checkpoint inhibitors - reduces multiple myeloma-associated tumour burden, bone damage and/or enhances T-cell-mediated anti-tumour immunity.

If successful, the findings of this PhD project have the translational potential to identify TRAF6 inhibition (in combination with immunotherapy) as a new, targeted combinational therapy for multiple myeloma. In the long term, and guided by these preclinical studies, we plan to conduct clinical trials in collaboration with Professor S. Danson (clinical oncologist, University of Sheffield, UK) to test the therapeutic efficacy of an appropriate TRAF6 inhibitor in multiple myeloma patients. Such studies will address an urgent, unmet clinical need, as acquired resistance to chemo- and immuno-therapy is a clinical problem in multiple myeloma patients.

Funding:

Self-funded / open to Home/EU and Overseas

Entry Requirements:

Candidates must have a first or upper second class honors degree. Laboratory hands-on experience in tissue culture techniques is desirable. Experience with transfection techniques and in vivo imaging would be advantageous.

Enquiries:

Dr Aymen Idris. Email:, Tel: 00441142713338, Website: https://www.sheffield.ac.uk/medicine/people/oncology-metabolism/aymen-i-idris

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please make sure you name both supervisors on your application form and put Oncology and Metabolism as the Department.

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