Follicular lymphoma is a cancer of B-lymphocytes which is diagnosed in approximately 2,200 patients in the UK each year. Despite recent advances in treatment, follicular lymphoma remains incurable, with some patients surviving only a few years. Tazemetostat is an existing drug that was recently developed for the treatment of this lymphoma. It works by blocking an enzyme EZH2 that chemically modifies DNA to control how genes are switched on and off, and is commonly mutated in follicular lymphoma. While it is an effective treatment, tazemetostat rarely gets rid of the disease altogether and only works for a relatively short time.
The aim of this project is to test combining other drugs with tazemetostat to make it work more effectively. The enzyme blocked by tazemetostat, EZH2, needs methyl groups to work. Lymphoma cells obtain these methyl groups from metabolism, which has been the focus of our recent research. Our group, in collaboration with Professor Karen Vousden from the Francis Crick Institute, has discovered that lymphoma cells need particular metabolic pathways to allow them to grow and survive (D’Avola et al. The Journal of Clinical Investigation 2022). Furthermore our recent work has shown that blocking these metabolic pathways is an effective treatment in pre-clinical models of lymphoma and a potential new therapy for patients. Therefore, we believe that combining tazemetostat with inhibitors of metabolism will make it more effective. We anticipate that our proposal will provide the evidence required to start a clinical trial of novel drug combinations for this lymphoma.
We will use in-vivo and in-vitro experimental techniques to study the relevant metabolic pathways in lymphoma cells and in biopsies from follicular lymphoma patients. The aim will be to understand the interaction between metabolism and epigenetics in lymphoma, and whether targeting metabolism can act synergistically to enhance the efficacy of tazemetostat for this cancer. The student will gain experience in a broad range of molecular and cell biology techniques including: mass spectrometry and metabolomics, immunoblotting, PCR, shRNA knockdown, cell culture, flow cytometry, chromatin immunoprecipitation, drug-testing toxicity, immunohistochemistry, genotyping and in-vivo drug delivery and analyses. All techniques are well established within the laboratory and the student will be supported by experienced post-doctoral researchers in addition to the supervisors.
The student will be based in the Centre of Haemato-Oncology at Barts Cancer Institute at Queen Mary, University of London in which the 1st and 2nd supervisors are faculty. This group of 15 academic staff and their teams, is one of largest units dedicated to blood cancer research in the UK. In addition, the academic staff comprise an equal mix of scientists and clinician scientists meaning that there is a strong emphasis on translational research and close links with St. Bartholomew’s hospital and the UK National Health Service. Furthermore, the 3rd supervisor is a senior group leader at the Francis Crick Institute, the single biggest biomedical research facility in Europe, giving the student access to the facilities and opportunities there, including core facilities, seminars, conferences and training events.
The supervisory team are committed to the training of a clinically qualified PhD student. Therefore, the primary supervisor would facilitate the student joining his lymphoma clinic at St. Bartholomew’s hospital for them to gain relevant clinical experience for part of the fellowship if they so wished. This would be dependent on their satisfactory progression and organised in such a way that it did not interfere with their PhD studies. A further important aspect is that the ultimate aim of this project is to set up a clinical trial of the proposed combination therapy. The supervisors plan to work with industrial partners to facilitate this during the project and would encourage the student’s involvement. This would involve attending the meetings with pharmaceutical companies, drafting the trial protocol and patient information leaflets, submitting applications to research ethics and governance committees, and liaising with patient and public involvement groups. Therefore we envisage that this project as a platform for the long term career development of the student, offering a range of opportunities in basic and translational science, along with experience in clinical trials and in clinical practise.
Funding Notes:
The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for a research studentship, for a clinically qualified candidate to commence in October 2023, leading to a PhD degree from The QMUL Faculty of Medicine and Dentistry.
This studentship will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. The Studentship will cover the successful candidate’s current clinical salary and will include PhD fees (at home fee rate) with up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.
Notice on Equality, Diversity and Inclusion:
Barts and The London School of Medicine and Dentistry aims to promote an organisational culture that is respectful and inclusive irrespective of age, disability, gender reassignment, ethnicity, marriage or civil partnership, pregnancy and maternity, race, sex and religion or belief. Moreover, it seeks to ensure that intersectionality is recognised, with explicit acknowledgement of the interconnected nature of social identities including race, class and sex, where these facets can create overlapping levels of discrimination or disadvantage.
Privacy Statement – sharing personal data with HARP
When you apply to the Trust for PhD support, or at any time afterwards, where you also apply to the Health Advances in Underrepresented Populations and Diseases PhD programme (“HARP”), the Trust will share your personal information with the Directors of HARP and with the other organisations involved in that programme, namely Queen Mary University of London, City University of London, Barts Charity, Barts Health NHS Trust and East London Foundation Trust. This may involve sharing your completed application forms, including equality monitoring information, as well as your name and contact details, your CV, details of your skills, education and experience, your proposed areas of study, and other information supporting your application.