PhD Study : Developing novel synergistic drug combinations with venetoclax in acute myeloid leukaemia

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

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