Development of novel inhibitors for GPX4 and the treatment of cancer by induction of ferroptosis

About the Project

Ewing Sarcoma is the second most common type of primary bone cancer affecting children. Whilst survival rates in patients without metastatic disease are approximately 60-70%, there are no targeted therapies to treat Ewing Sarcoma, with current treatment consisting of broad chemotherapy followed by radiation or surgery. Glioblastomas are grade 4 brain tumours for which there is no cure, with treatments used to slow cancer growth and reduce symptoms. The average survival with treatment for patients with glioblastoma is 12-18 months, with fewer than 5% of patients surviving more than 5 years.

Treatment and survival for both these diseases would be improved through the development of a targeted treatment. Inducing ferroptosis is considered an effective treatment strategy for refractory cancers such as glioblastoma and Ewing Sarcoma. Ferroptosis is an alternative form of cell death to apoptosis which can be triggered by inhibition of the protein Glutathione Peroxidase 4 (GPX4), a selenoenzyme.

The proposed project will validate GPX4 as a cancer target for Ewing Sarcoma and glioblastoma through genetic means and through inhibition. Building on this, it will develop and characterize novel selenocysteine-targeting covalent inhibitors of GPX4. This will entail integrating the designed and optimised covalent warheads that selectively bind to selenocysteine over cysteine: with NMR and LC-MS studies used to explore the reactivity and selectivity. A design-make-test cycle will be used to explore the SAR of GPX4 covalent inhibitors and optimise a covalent inhibitor for the protein using cell-based screening techniques. These inhibitors will be used for further characterisation in cellular systems and activity-based proteomic profiling to demonstrate the potential of GPX4 as a therapeutic target for Ewing Sarcoma and glioblastoma. The biology of the ferroptotic pathway will be explored with genetic (siRNA, shRNA,CRISPR) knockdown of pathway components to complement pharmacological interventions.

The project will provide multidisciplinary training in experimental techniques across chemistry and biology. Hands-on experience in cellular biology and activity-based proteomic profiling will be provided by Rankin and Hickson. Skills in synthetic medicinal chemistry, encompassing screening conditions, computational modelling and compound design will be provided under the guidance of Waring and Stewart.

This training will provide a highly desirable skill set involving the ability to carry out both biology and chemistry, thus enabling research at the chemistry-biology interface, a critical skills gap. Additionally, a comprehensive programme of transferrable skills training will be provided alongside the support to develop an awareness of responsible research and management of EDI, providing a holistic development programme for a successful future career.

Funding

Students who have, or are expecting to attain, at least an upper second-class honours degree (or equivalent) in a relevant subject, are invited to apply. Funding is available for Home (UK) students to cover tuition fees, a tax-free stipend at the UKRI rate (indicative amount in year 1 in 2026-27, £21,805) and research costs, for four years. Applicants normally required to cover International fees will have to cover the difference between the Home and the International tuition fee rates. There is no additional funding available to cover NHS Immigration Health Surcharge (IHS) costs, visa costs, flights etc.

Funding for this studentship is awarded on a competitive basis and is not guaranteed; availability will depend on the outcome of the selection process and subject to final approval by the University.

HOW TO APPLY

Please complete the following application form

Applicants can only apply for 1 project; any additional applications will not be accepted.

Applicants should send the following documents to FMSstudentships@newcastle.ac.uk:

• a CV (including contact details of at least two academic (or other relevant) referees).
• a Cover letter – stating your project choice, as well as including additional information you feel is pertinent to your application.
• copies of your relevant undergraduate degree transcripts and certificates.
• a copy of your IELTS or TOEFL English language certificate (where required)
• a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE

Please submit your documents in the following format only:

• each document should be submitted as a separate attachment and should be named as follows: candidate surname, candidate name – document type. For example: Jones, Jamie – CV; Jones, Jamie – cover letter.
• Please submit .pdf documents where possible for your CV, cover letter, transcripts and certificates. Do not submit photos of certificates.
• Do not combine documents into one pdf. You may zip separate documents into a zip file to send via email if required.
• When emailing your application, please use the email subject header: FMS PhD Application 2026

Applications not meeting these criteria may be rejected.

Informal enquiries may be made to the lead supervisor of the project you are interested in.

The deadline for all applications is 12 noon BST (UK time) on Wednesday 20th May 2026