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Examining the potential for low-dose methotrexate for the treatment of JAK/STAT-related diseases

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  • Full or part time
    Dr M Zeidler
  • Application Deadline
    Applications accepted all year round

Project Description

This project seeks to undertake pre-clinical and clinical trial-related research designed to characterise the potential for repurposing the generic drug methotrexate (MTX) for the treatment of diseases characterised by the ectopic activation of the JAK/STAT signalling pathway. We have previously shown that MTX is able to suppress JAK/STAT activity in both Drosophila and human cells (Thomas et al 2015) and have very recently published a study showing that MTX can also strongly reduce the disease phenotypes in a humanised mouse model of polycythemia vera (PV) – a human blood cancer triggered by gain-of-function mutations in human JAK2 (Chinnaiya 2017). In the light of these results, we are currently partnering with Rosemont Pharmaceuticals (Leeds) and the Birmingham Clinical Trials Unit to undertake a small scale, Phase II safety and efficacy clinical trial of low-dose MTX in PV patients. As part of this trial we also seek to undertake further research into the pharmacodynamics of MTX, its effectiveness in mouse and human samples and the biochemistry of its mechanism of action. These approaches will use blood from patients participating in the clinical trial, as well as humanised mouse models of PV and cutting edge biochemical techniques to characterise protein:drug interactions and JAK2 kinase activity. The data generated by this project will ultimately be used to inform clinical guidance and to support applications to the regulatory authorities (EMA, FDA) which are required to formally licence MTX for the treatment of PV. As such, this project has the potential to produce substantial impact for a significant patient population with clear unmet clinical needs. Given the need to interact with patients taking part in the clinical trial, a candidate would ideally have a clinical background in haematology and/or oncology. They would also have a strong interest in developing their research skills into new and challenging areas.

Funding Notes

Applications from self-funded students or students with secured funding are also welcome.

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD Studentship, you must complete the University's application form using the following link: http://www.sheffield.ac.uk/postgraduate/research/apply/applying
*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130078

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

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

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