The Precision of New Therapies for Intraoperative Brain Cancer Surgery
Prof M Vendrell, Dr P Brennan
About the Project
The clinical need. Glioblastoma is the most aggressive primary brain tumour and the cancer with the most years of potential life lost in adults. Even with optimal surgery, chemotherapy and radiotherapy, the median survival is only around 15 months. The infiltrative nature of glioblastoma and the presence of cancerous cells in proximity to untouchable (eloquent) vital structures precludes complete tumour resection for improved outcomes. Light-guided surgery with 5-aminolevulinic acid (5-ALA) can aid surgeons to improve maximum safe resection, but 5-ALA lacks sensitivity and specificity for tumour cells. New technologies are needed to optimise tumour resection and ablation without damaging healthy tissue.
Photodynamic therapy. Photodynamic therapy (PDT) is clinically utilised for the ablation of cells via oxidative stress caused by light-activatable photosensitisers (PS). PDT is not currently available for routine treatment of glioblastoma, but it could be used to target residual tumour cells close to vital structures as more than 98% of brain tumours recur within few mm of the resection margin. 5-ALA is currently under evaluation in clinical trials as a PDT agent against glioblastoma (NCT03048240), where resection is carried out and PDT is applied to the resection cavity. 5-ALA is an amino acid that is metabolised intracellularly to generate protoporphyrin IX, a natural PS that generates singlet oxygen after light irradiation. Because the metabolic rate in cancerous cells is accelerated when compared to healthy tissues, 5-ALA can generate more protoporphyrin IX in tumours than in healthy cells. However, 5-ALA has two major limitations as a PDT agent for ablation of glioblastoma: 1) 5-ALA is administered orally and it takes several hours to metabolise into protoporphyrin IX. This time can vary between patients (between 2 and 5 h), making the dosing of 5-ALA difficult to optimise in a patient-specific manner, particularly once the surgical intervention has started; 2) the limited sensitivity and specificity of 5-ALA results in off-target localisation and failure to achieve maximal safe tumour resection. In addition, limited access to cost-effective devices for intracranial illumination hinders the advancement of PDT for the treatment of glioblastoma. Standardised systems for reliable activation of the PS would increase the usability of PDT in surgical interventions, making it a more practical and widely used approach for the treatment of glioblastoma.
To improve upon the shortcomings of existing PDT agents, we are developing new PS that can be rapidly (i.e., within minutes) and selectively taken up by glioblastoma cells after topical administration during surgical interventions. We can couple these new PS to suitable illumination devices for the delivery of safe and non-toxic light or sound waves for effective surgical intervention. This new approach will allow clinicians to optimise tumour ablation in a patient-specific manner, maximising sensitivity and specificity while minimising off-target accumulation and potential side effects.
The main objectives are:
1. To evaluate novel metabolite-PS conjugates and to identify those that are selectively taken up by transporters expressed in human glioblastoma cells.
2. To optimise the properties and delivery of selected metabolite-PS conjugates for PDT on human glioblastoma with minimal off-target localisation.
Relevance to cancer and the research themes and strategic areas of the Centre:
This project aligns with the research ‘Brain tumours’ and will exploit the combined expertise of Brennan (Reader and Honorary Consultant Neurosurgeon), Vendrell (Professor and Head of Chemical Imaging Group). Brennan has a current program of work that focuses on the development of translational biomarkers to improve the outcomes of brain cancer surgery. Vendrell has strong expertise in optical imaging probes, with particular interest in the development of in situ biomarkers for disease progression and patient stratification. Vendrell leads a prestigious ERC Consolidator Grant-funded research program on non-invasive chemical tools to interrogate cell function in real time.
This is a highly interdisciplinary project at the interface between chemical and cancer biology which will lead to new biomarkers for high precision intraoperative imaging of brain cancer. The project builds on the cross-disciplinary collaboration, and the student will strongly benefit from this multidisciplinary environment by working in labs with complementary expertise. Specifically, they will get training in chemical biology (e.g., probes, spectroscopy), metabolomics and cell biology (e.g., mass spectrometry, cell-based assays, flow cytometry, immunohistochemistry, in vitro cultures) as well as in data analysis and data mining for decision-making tools with enhanced precision.
Techniques/model systems to be used and training to be offered:
Generic and transferable skills provided by the supervisory team:
- Design and characterisation of light-activatable metabolites.
- Cell culture, microscopy, flow cytometry, functional assays and immunohistochemistry.
- Assessment of optimal agents in ex vivo human tissues.
- Image analysis (qualitative and quantitative).
- Research ethics and health and safety skills.
- Target Product Profile based on current standard of care, health economics data and technical feasibility.
- Participation in the development of marketing strategy through competitive landscape and future emerging technologies (with Medical Innovations Team).
- Study IP landscape and freedom to operate. Secure emerging IP, including paper and patent writing.
- Communication skills.
Up to 4 studentships are available to start in September 2023 for outstanding applicants with a stipend of £21,000 p/a. These 4 STUDENTSHIPS are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students for Edinburgh lead projects will be registered for their degree in Edinburgh and will undertake their project in Edinburgh.
Candidates should hold at least an upper second-class degree in a relevant subject and comply with University of Edinburgh English language requirements.
For further information on how to apply, please visit: https://www.ed.ac.uk/cancer-centre/graduate-research-and-training/cancer-research-uk-phd-programme