Finding the Achilles’ heel of drug-resistant breast cancer: exploiting synthetic lethal vulnerabilities in transcription factor signalling
Closing date: 23/11/2026
Clinical Research Training Fellowship: Finding the Achilles’ heel of drug-resistant breast cancer: exploiting synthetic lethal vulnerabilities in transcription factor signalling
Lead Supervisors: Dr Sankari Nagarajan
Co-Supervisors: Dr Anne Armstrong, Dr Sumitra Mohan, Professor Andrew Sharrocks, Dr Andrew Gilmore, Dr Bruno Simoes
Applications Deadline: 12:00pm Monday 23rd November 2026
Interviews: Friday 5th February 2027 (in Manchester)
Start date: September 2027
Project Keywords: Breast cancer, epigenetics, transcription factors
Research Opportunity: Clinical Research Training Fellowship leading to the award of PhD
Project Outline
Breast cancer is the most common cancer in women. Every year in the UK, around 55,000 patients are diagnosed with breast cancer, and only 23% of them have preventable disease. Around 70% of breast cancers are driven by the estrogen receptor (ER). Drugs which block the effects of the estrogen receptor reduce the risk of recurrence. Although they are initially effective, the risk of recurrence persists for at least 20 years after diagnosis, leading to incurable disease and death. Hence, understanding how a drug fails is vital to increase patient survival.
Gene expression plays an essential role during cancer progression. This process is regulated by various means, importantly by proteins that can open/close chromatin, called chromatin remodeller complexes (CRC). CRC proteins are inactivated by mutations in treatment-resistant breast cancers, leading to a poorer outcome. We found in our previous study that cells stop responding to these treatments when they lose CRC. We also identified a specific class of transcription factors that are hyperactivated in patients with ER and CRC loss. We believe that their hyperactivity causes these patients to stop responding to drugs. Hence, targeting these transcription factors may affect cells with deregulated signalling due to CRC or ER loss; therefore, the strategy can be used to sensitise drug-resistant cancers without affecting normal cells.
In this study, the student will test this idea by modifying cancer and normal cells to reduce transcription factor protein levels during existing therapies, and will identify the important proteins activated by these transcription factors and drugs that block them. These drugs might stop cancer growth in patients with reduced CRC and ER levels, revealing opportunities for personalised medicine and targeted therapeutics that could improve patient survival. The research will provide opportunities to advance drug discovery/development, thereby potentially positioning the clinical student’s development towards clinical trials.
Applications for this project are now open. Please complete your application on The University of Manchester website.
About Dr Sankari Nagarajan (project Lead Supervisor)
The Nagarajan lab is interested in unravelling the mechanisms of enhancer regulation and the role of transcription factors in mediating the progression to drug resistance and metastasis in aggressive cancers. We utilise single cell analyses, functional genomic technologies, quantitative chromatin-based proteomics and CRISPR-Cas9 assays to decipher the mechanisms of transcription. We work on the following projects:
1. Understanding the role of chromatin-associated proteins in driving endocrine resistance in breast and prostate cancers
2. Deciphering the activity of enhancers and transcription factors regulated by chromatin remodelling complexes
3. Single cell epigenomics to investigate the molecular mechanisms of metastasis in aggressive cancers
4. Enhancer-derived RNAs as markers for enhancer regulation in aggressive breast cancers
Key information
Before submitting an application, please ensure you have read the information below about the funding arrangements and eligibility for our Clinical Research Training Fellowships.
We also encourage you to get in contact with the lead supervisor to discuss the project and any particulars.
Further information is available on the Clinical Research Training Fellowships webpage.
The clinical fellowships are usually tenable for three years, although in certain circumstances they may be four years duration. The Fellowship covers:
- running expenses,
- an appropriate salary in line with the applicant’s current NHS salary and grade
- full coverage of University PhD fees at the UK/home fee rate.
International Candidates
The University of Manchester aims to support the most outstanding applicants from outside the UK.
We are able to offer a limited number of bursaries to high-performing EU and international candidates, covering PhD fees only. Bursaries do not include financial support for visa/health surcharges.
We assess each EU and international candidate’s suitability for a bursary at the application and interview stages.
You must be a post-registration clinician, and ideally have a specialist post in a related subject, to apply for our Clinical Research Training Fellowships.
Applicants must hold an MBChB degree or an equivalent medical qualification. You should also hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.
It is generally expected that CRTFs will return to a training programme in the UK upon completion of their research degree.
International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University’s Country Specific information page.
Applications for this programme are now open. Please submit your application on The University of Manchester application portal.
Key dates
- Applications open: Monday 5th October 2026
- Application deadline (all projects): 12:00pm Monday 23rd November 2026
- Clinical Interviews: Friday 5th of February 2027 (in Manchester)
- Start date: September 2027 with flexible starts for clinicians
Useful Links
Submit your application
Interested in applying for this opportunity? Submit your application on The University of Manchester application portal.
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