PhD Study : Identifying molecular dependencies in NRAS-mutant leukaemia

Summary

Acute myeloid leukaemia (AML) is a type of blood cancer of myeloid lineage that is characterised by the rapid proliferation and accumulation of immature cells in the bone marrow. There are approximately 3,100 new cases of AML diagnosed in the UK each year and 2,600 deaths1. Recent whole genome sequencing efforts in both childhood2 and adult3 AML have defined the driver landscape in the disease which will further support patient stratification and targeted drug development.

Oncogenic mutations in NRAS are highly prevalent in AML, especially in the paediatric disease (~30% of cases) compared to adult AML (~10%), despite the low somatic mutational burden2. NRAS normally functions by transducing signals from activated receptors to the nucleus, where it regulates cell growth and survival. Mutant NRAS encodes a protein which is locked in the ‘on’ conformation, resulting in sustained growth and survival of the leukemic cells. While representing an exciting therapeutic target, directly targeting oncogenic NRAS, or any of the Ras family members, is complex and no clinical inhibitors currently exist4.

This PhD studentship aims to identify genes that mutant NRAS may depend on for survival and understand their role in the development of AML. To do this, the student will first investigate molecular exclusivities with mutant NRAS that have recently been identified as part of the Beat AML programme2. The student will then perform a genome-wide synthetic lethality screen using CRISPR-Cas9 technology in clinically relevant NRAS mutant cell models to identify genes, that when knocked out, result in the death of NRAS mutant AML cells. Genes that are essential for the survival of NRAS mutant AML cells will be validated and studied in a variety of murine and human models and in patient samples.

The overall aim is to identify molecular dependencies in NRAS-driven leukaemia that may present an alternative therapeutic strategy to directly targeting mutant NRAS. This project and will benefit from a range of approaches, such as CRISPR-Cas9 knockout screening, molecular biology, genomics, FACS, computational biology and murine models.

References

¹ Cancer Research UK.

² Bolouri et al. 2018. Nature Medicine, 24:103-112.

³ Tyner et al. 2018. Nature, 562: 526-530.

⁴ Downward 2015. Clinical Cancer Research, 21:1802-1809.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• First Class Honours (1st) Degree
• Masters at 65%
• Research project completion within taught Masters degree or MRES
• Practice-based research experience and/or dissemination
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications - peer-reviewed
• Experience of presentation of research findings
• A comprehensive and articulate personal statement
• Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living