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Funded PhD Opportunity

Developing novel synergistic drug combinations with venetoclax in acute myeloid leukaemia

Subject: Biomedical Sciences


Summary

Acute myeloid leukaemia (AML) is an aggressive blood cancer that arises from impaired differentiation of hematopoietic progenitor cells. While many AML patients respond to induction chemotherapy, relapse and refractory disease is common. Indeed, only ~20% of patients survive for 5 years or more following diagnosis1. Treatments for AML, which affects both children and adults, have remained largely the same since the 1960s.

These therapies are associated with severe side effects. Members of the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of apoptosis. Consisting of both proapoptotic and prosurvival proteins, cancer cells can evade cell death and survive by reliance on prosurvival proteins, such as BCL-2, MCL-1 and BCLXL, creating a therapeutic vulnerability. Venetoclax (ABT-199), an orally bioavailable selective BCL-2 inhibitor, was developed in 20132 and found to provide remarkable efficacy and improvements in progression-free survival in relapsed chronic lymphocytic leukaemia (CLL)3. Based on these results, venetoclax was approved by the FDA in June 2018 for patients with CLL4, and in November 2018 for AML (in combination with chemotherapy)5.

While venetoclax does offer a potential significant advance in the AML field, there is an unmet clinical need to improve its efficacy, without increasing toxicity. This PhD studentship aims to discover and develop novel drug combinations with venetoclax in AML. The student will perform a high-throughput screen of >800 approved compounds in combination with low dose venetoclax in clinically relevant AML cell models. Drug hits that generate synergy with venetoclax with be deconvoluted and validated in expanded murine and human cell models and toxicities studied in a range of normal cells.

Mechanistic experiments will be performed to understand how the novel combination functions at a genetic and cellular level and the combination/s investigated in pre-clinical experiments using both transplanted human cell lines and patient-derived xenographs. Finally, venetoclax resistant AML cells will be developed which will be used to study mechanisms of resistance and for follow up screening. This project and will benefit from a range of approaches, such as advanced drug screening, molecular biology, genomics, FACS, computational biology and murine models.

References

1 National Cancer Intelligence Network and Public Health England, 2014.

2 Souers et al. 2013. Nature Medicine, 19:202-208.

3 Seymour et al. 2018. New England Journal of Medicine, 378:1107-1120.

4 https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610308.htm.

5 https://www.onclive.com/web-exclusives/fda-approves-frontline-venetoclax-in-aml.


Essential criteria

  • To hold, or expect to achieve by 15 August, an Upper Second Class Honours (2:1) Degree or equivalent from a UK institution (or overseas award deemed to be equivalent via UK NARIC) in a related or cognate field.
  • 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

    The University offers the following awards to support PhD study and applications are invited from UK, EU and overseas for the following levels of support:

    Vice Chancellors Research Studentship (VCRS)

    Full award (full-time PhD fees + DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £15,000 maintenance grant 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.

    Vice-Chancellor’s Research Bursary (VCRB)

    Part award (full-time PhD fees + 50% DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £7,500 maintenance grant 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.

    Vice-Chancellor’s Research Fees Bursary (VCRFB)

    Fees only award (PhD fees + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees 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.

    Department for the Economy (DFE)

    The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £ 15,009 per annum for three years. EU applicants will only be eligible for the fee’s component of the studentship (no maintenance award is provided). For Non-EU nationals the candidate must be "settled" in the UK. 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.

    Due consideration should be given to financing your studies; for further information on cost of living etc. please refer to: www.ulster.ac.uk/doctoralcollege/postgraduate-research/fees-and-funding/financing-your-studies


Other information


The Doctoral College at Ulster University


Reviews

My experience has been great and the people that I have worked with have been amazing

Kieran O'Donnell - 3D printing of biological cells for tissue engineering applications

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Completing the MRes provided me with a lot of different skills, particularly in research methods and lab skills.

Michelle Clements Clements - MRes - Life and Health Sciences

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Throughout my PhD I’ve been provided with continuous support and guidance by my supervisors and the staff at the University.I’ve also received many opportunities to further enhance my professional development in the form of teaching experience and presenting my work at conferences which will aid in my pursuit of a career in academia or industry.

William Crowe


Key dates

Submission deadline
Monday 18 February 2019

Interview Date
w/c 11, 18 and 25th March 2019


Applying

Apply Online  


Campus

Magee campus

Magee campus
A key player in the economy of the north west


Contact supervisor

Dr Kyle Matchett


Other supervisors

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