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  Characterising and targeting chemo-resistant acute myeloid leukaemia (AML) cells utilising a novel in vitro model of the bone marrow microenvironment


   Post-graduate Research

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  Dr Eleni Ladikou, Prof Andrea Pepper, Dr Fabio Simoes  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

About the Project

Applications are invited for a 3.5-year funded PhD studentship at Brighton and Sussex Medical School.

Project details:

Acute myeloid leukaemia (AML) is the most common type of acute leukaemia in adults, with its incidence increasing with age1. According to Cancer Research UK, there are 3000 new cases each year and 2700 deaths2. AML remains a therapeutic challenge due to its aggressiveness and genetic/phenotypic heterogeneity3, 4. Although 80% of patients can initially achieve a complete remission, the long-term disease-free survival (DFS) is only 40% at 6 years with a 10% 5-year survival rate from first relapse 5. Therefore, relapse after initial response to chemotherapy remains a serious clinical challenge requiring new therapeutic strategies.

The persistence of chemo-resistant cells in the protective bone marrow (BM) microenvironment (BMME) following standard therapies is a key challenge that must be overcome to enable successful treatment of AML patients The aim of the project is to characterise these chemo-resistant AML cells and identify novel druggable targets to increase their vulnerability to therapy.

We have already developed an in vitro multi-cellular co-culture system that mirrors the adhesive and chemo-protective nature of the AML BMME; the BMAS (PhD Dr Eleni Ladikou). Using this system, we have demonstrated that a proportion of adherent AML cells remain viable in the presence of the commonly utilised chemotherapeutic agent, cytarabine. Utilising the BMAS, the successful candidate will identify novel and specific druggable pathways that can be leveraged to increase the vulnerability of this resistant cell population to therapy. They will use multiple approaches to achieve this, including transcriptomics (scRNA sequencing), phenotypic characterisation (flow cytometry) and functional assays (differentiation markers, cell cycle, proliferation and colony forming unit assays) in both cell lines and primary patient cells. The aim is to find either a common target within different patients or potentially patient-specific targets. Finally, the impact of modulating identified targets on the resistant leukaemic cells will be tested in vitro using targeting therapies (if they are available), or siRNA knock-down.

Research Environment: The successful candidate will be integrated into the rapidly expanding haemato-oncology team at BSMS led by Professors Chris and Andrea Pepper (https://www.pepper.science) working closely with the computational biology team led by Dr Simon Mitchell (https://mitchell.science) and Dr Fabio Simoes, who leads the in vivo work. The project will be co-supervised by Dr Eleni Ladikou, Professor Andrea Pepper (who supervised Dr Ladikou’s PhD) and the team’s new lecturer, Dr Fabio Simoes. Dr Ladikou, who established the system to be used in the project, is uniquely placed to lead this study and impart the knowledge and expertise she gained during her PhD studies to the successful candidate. Furthermore, she is a clinical academic and will be ideally placed to recruit AML patients into the study.

The candidate will also integrate into the Haematology Research Group, which spans the University of Sussex, University of Brighton and BSMS. The project offers a wide range of training opportunities, and the student will be able to acquire essential skills from a variety of areas including cell biology, cell signalling, drug targeting bioinformatics, and translational haemato-oncology. This should provide the successful candidate with critical skills and substantial experience to make them a highly competitive candidate for a postdoctoral research position, especially in the field of translational oncology. The candidate will also have the opportunity to engage with patients and their families at research open days and the clinical team at the Royal Sussex County Hospital and Eastbourne hospital, who will help obtain patient samples for laboratory experiments.

Entry requirements: This studentship starting on 1st October 2024 is suitable for those with background in biological, cancer sciences or a related discipline. We invite applications from students who hold, or expect to obtain, a first or upper second-class undergraduate degree or equivalent, in an appropriate subject, from a recognised academic institution. This studentship is only open to UK citizens or EU citizens who have pre-settled or settled status.

How to apply: Applicants must apply through the University’s application Portal (StudentView (brighton.ac.uk) where they can submit a CV and complete the application form. Please select “Doctoral College” as the School, and select the studentship listed in order to apply. The deadline for applications is 12th April 2024. Interviews will be held in May 2024. Informal enquiries are welcome and should be submitted to Dr Eleni Ladikou ([Email Address Removed]). Please note, this studentship is one of three studentships being simultaneously advertised by researchers within the Haematology Research Group (https://www.bsms.ac.uk/research/clinical-and-experimental-medicine/cancer/hrg/haematology-research-group.aspx). We welcome parallel applications to these exciting training opportunities.

Biological Sciences (4)

Funding Notes

This is a 3.5-year PhD studentship funded by Brighton and Sussex Medical School and Sussex Cancer Fund, starting on 1st October 2024. Funding will cover tuition fees for UK students (at the Home rate), a stipend at the UKRI rate and a research allowance which will cover research running costs. International applicants are welcome to apply but will be required to cover the difference between Home and International fees.

References

1. Schlenk RF. Acute myeloid leukemia: Introduction to a series highlighting progress and ongoing challenges. Haematologica. 2023 Feb 1; 108(2):306-7.
2. UK CR. [Internet]. [accessed 2023 14/04]. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/leukaemia-aml#:~:text=In%20females%20in%20the%20UK%2C%20acute%20myeloid%20leukaemia%20accounts%20for,89%20(2017%2D2019).
3. Quek L, Otto GW, Garnett C, Lhermitte L, Karamitros D, Stoilova B et al. Genetically distinct leukemic stem cells in human cd34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med. 2016 Jul 25; 213(8):1513-35.
4. Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A et al. Clonal heterogeneity of acute myeloid leukemia treated with the idh2 inhibitor enasidenib. Nat Med. 2018 Aug; 24(8):1167-77.
5. Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG et al. Randomized comparison of dat versus ade as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the medical research council's 10th aml trial (mrc aml10). Adult and childhood leukaemia working parties of the medical research council. Blood. 1997 Apr 1; 89(7):2311-8.
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