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Understanding myeloma cell - microenvironment interactions and their role in immunomodulatory drug resistance


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  Dr Charlotte Pawlyn, Dr O Rossanese  No more applications being accepted  Funded PhD Project (Students Worldwide)

London United Kingdom Biochemistry Cancer Biology Cell Biology Molecular Biology Biological Sciences

About the Project

Project Description 

The bone marrow cancer multiple myeloma remains incurable despite advances in therapy. Immunomodulatory drugs (IMiDs) are the current backbone of standard and experimental combination therapies at all stages of disease. Understanding IMiD resistant and refractory states is therefore imperative to help us improve patient outcomes. Resistance to IMiDs is likely to be multifactorial with both myeloma cell intrinsic and extrinsic factors. Myeloma cell intrinsic mechanisms such as mutations and deletion of CRBN have been described and other factors such as epigenetic modifications are thought to play a role. We have generated in vitro cell line tools that mimic both CRBN mutated and unmutated resistant states.

In patients, however, myeloma cells exist in a complex ecosystem in the myeloma bone marrow microenvironment. Previous studies suggest that the interaction with the bone marrow stroma/fibroblasts may also contribute to therapy resistance by direct and indirect communication leading to re-wiring of signalling pathways, but the protein level changes that are responsible for this are not well understood. Whether resistance results from soluble factor transmission, exchange or direct cell-cell contact is also unclear.

This project aims to study these myeloma cell - stroma interactions and how they contribute to IMiD resistance.

  1. Analyse proteomic, transcriptomic and epigenetic changes induced in myeloma cells by direct and indirect co-culture with bone marrow stroma.
  2. Assess the impact of co-culture on IMiD induced neosubstrate degradation and myeloma cell viability responses to IMiDs.
  3. Validate findings from Aims 1 and 2 and explore further in patient derived stroma and myeloma cell models.

Depending on the interests and qualifications of the candidate as well as progress within the group prior to the start date, the scope and aims of the PhD will be tailored accordingly.

Keywords

  • Cancer Therapy
  • Mechanisms of drug resistance
  • Microenvironment interactions
  • Proteomics
  • Blood cancer

PhD Studentship start date

If the successful candidate is able, this PhD Studentship will commence in March 2022.

Candidate profile

Candidates must have a First class or Upper Second class BSc Honours/MSc in biological sciences.

How to apply

To view the full project proposal and details on how to apply using our online recruitment portal, please go to icr.ac.uk/phds. Please ensure that you read and follow the application instructions very carefully.

Please note we only accept applications via the online application system apply.icr.ac.uk.

Applications close at 11:55pm UK time on 14 November 2021.


Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK and EU/overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world. We particularly welcome applicants from British Black and ethnic minority backgrounds, as they are under-represented at PhD level within the ICR and nationwide.
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