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Research Assistant/Associate- Drug resistance mechanisms in relapsed Acute Lymphoblastic Leukaemia

Newcastle University

Location: Newcastle upon Tyne
Salary: £31,396 to £44,263 per annum. Salary and grade will be commensurate with qualifications and experience. See advert text for further details
Hours: Full Time
Contract Type: Fixed-Term/Contract
Placed On: 17th June 2024
Closes: 20th June 2024
Job Ref: 27259

Company description:

We are a world class research-intensive university. We deliver teaching and learning of the highest quality. We play a leading role in economic, social and cultural development of the North East of England. Attracting and retaining high-calibre people is fundamental to our continued success.

Job description:

The Role


You will take ownership and deliver this new and exciting research project within the time limits specified by the GOSH Charity project grant. You will receive supervision and support from 5 principal investigators based at the Newcastle University Centre for Cancer and York University. You will have access to the full suite of infrastructure required to successfully complete this project. You will work in the vibrant and stimulating research environment at the Wolfson Childhood Cancer Research Centre. Attendance and presentation of research progress at inter / -national conferences will be strongly encouraged.

Our research groups aim to unravel drug resistance mechanisms in relapsed Acute Lymphoblastic Leukaemia and harness this knowledge to develop novel therapies in relevant preclinical models. This research has already led to the implementation of Selumetinib and Dasatinib in early phase clinical trials. Selumetinib in combination with Dexamethasone is undergoing evaluation for Ras mutant ALL, whereas Dasatinib in combination with Dexamethasone will be tested in cortical T-ALL. (PMID: 32139432, PMID: 30655370). Interestingly, we have observed drug synergy between these small molecule inhibitors and Dexamethasone resulting in reversal of glucocorticoid (GC) resistance. This is relevant for patients with relapsed ALL who often do not respond to Dexamethasone anymore. This project aims to elucidate the molecular mechanism underlying the resensitisation to GC with the ultimate aim the development of a therapy which can override GC resistance at relapse and thus improve treatment response and outcomes.

This project will take a two-pronged approach to investigate molecular determinants of GR function. Firstly, we will employ ChIP-sequencing to explore GR binding sites and histone modifications at these sites. Secondly, we will catalogue the GR interactome in the setting of the above-mentioned drug combinations. For this purpose, we will use our in-house developed APEX2-/TurboID peroxidase-directed proximal biotinylation assay. The candidate will define the interactome and identify differential chaperone recruitment to the GR complex in function of selected drug pressure. The nuclear GR interactome will be analysed using R and SUPPA2 for global splicing analysis. The functional role of candidate proteins will be validated using a variety of techniques, including chromatin and RNA immunoprecipitation, CRISPR knock-out and/or small molecule inhibitors. Ultimately, we are aiming to develop a strategy to reverse Dexamethasone resistance, increase cell death and improve treatment response and outcomes for patients with drug resistant ALL/LBL.

This post is fixed term, fixed term until 31/03/2027.

For informal enquiries contact: Dr Frederik W van Delft at Frederik.van-delft@ncl.ac.uk.

Find out more about the Faculty of Medical Sciences here:
https://www.ncl.ac.uk/medical-sciences/.

Find out more about our Research Institutes here:
https://www.ncl.ac.uk/medical-sciences/research/institutes/

As part of our commitment to career development for research colleagues, the University has developed 3 levels of research role profiles. These profiles set out firstly the generic competences and responsibilities expected of role holders at each level and secondly the general qualifications and experiences needed for entry at a particular level.

The post is subject to Medical clearance.

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