Ex vivo testing of fatty acid oxidation inhibitors to target chemotherapy resistant ovarian cancer (Dr Mara Artibani)

PROJECT TITLE

SUPERVISORS

• Dr Mara Artibani 
• Professor Hagan Bayley

DESCRIPTION OF PROJECT

Worldwide, every two minutes, a woman is diagnosed with ovarian cancer. More than 55% of them will die within 5 years and this low survival is due to two factors: we lack efficient screening tests, therefore we diagnose late; despite a good initial response to treatment, 80% of women will relapse within 18 months and will have repeated recurrences with progressively shorter interval time. Despite some recent progress, an efficient screening tool for ovarian cancer is at least a decade away from clinical implementation.

The obvious alternative strategy to improve survival is try to avoid, or at least delay, relapse: this could be achieved by targeting the chemotherapy resistant cells that survive treatment before they can reinitiate the tumour. PARP inhibitors are drugs recently approved as maintenance therapy to help keep ovarian cancer from coming back. They hold good promise, but come with significant caveats: they are more likely to be effective in tumours that carry mutations in certain DNA repair genes, they are expensive and patients will eventually become resistant.

To avoid these limitations and find alternative treatments, we have fully characterised the chemotherapy resistant cells found in women who responded exceptionally well to treatment. Unlike normal cancer cells, this resistant cell population relies heavily on fat for energy production; we showed that their metabolic preference can be targeted therapeutically with specific inhibitors and we have obtained promising results with marketed drugs currently used to treat angina and epilepsy. These results were achieved in our 2D model of MRD as well as in micro-tumours, an innovative 3D culture achieved through a novel droplet microfluidic system, which guarantees high-throughput and uniformity of size, and is therefore ideal for drug screening.

This project will focus on improving the micro-tumours by adding key elements of the tumour microenvironment, such as adipocytes and immune cells, in order to fully recapitulate MRD biology. The new model will then be used to validate the efficacy of our compounds in a more clinically relevant setting, using also primary tumours obtained from ovarian cancer patients.

Ultimately, we aim to achieve two goals: 1) create an accurate model of MRD that could be easily adapted to screen anti-MRD drugs for other cancer types; 2) assess the feasibility of a clinical trial where low-cost, readily available drugs could be repurposed and provide a cost-effective approach to improve survival for all ovarian cancer patients.

TRAINING OPPORTUNITIES

The supervisors will provide comprehensive support throughout the project, addressing both clinical and scientific aspects with regular meetings. The student will attend weekly lab meetings where members provide progress reports on their project, discuss technical problems or deliver a journal club.

The student’s comprehensive training opportunities will include: 1) lab and departmental inductions on Health and Safety, Risk Assessments, Human Tissue Act, Good Clinical Practice, Good Research Practice and Information Security & Data Privacy Awareness, which will enrich the student’s comprehension of Research Governance; 2) practical training on how to use microfluidic devices for micro-tumour fabrication, Seahorse XF Analyser for energy metabolism experiments, IncuCyte for automated cytotoxicity assays, alpha300R Confocal Raman Microscope for live real-time single-cell metabolic analysis, bioinformatics training for RNAseq analysis.

Additionally, the student will engage with the Oxford University Careers Service to receive guidance on refining their resume and improving interview skills. They will also participate in workshops on how to deliver effective presentations for audiences with a range of difference scientific backgrounds and develop essential skills for PhD students, including thesis writing and prioritising new directions and experiments.

These opportunities will empower the student to adapt to the dynamic and ever-evolving pathway of PhD research.

FUNDING INFORMATION

This project has been shortlisted for a full 4-year NC3Rs PhD studentship (final outcome to be announced at the end of October 2024).

HOW TO APPLY

To apply for this research degree, please click here.