1st Supervisor: Jonathan Shapey, King’s College London
2nd Supervisor: Graeme Stasiuk , King’s College London
Clinical Supervisor: Prof. Keyoumars Ashkan, KHP Lead for Neuro-oncology
Industry Supervisor: Dr Michael Ebner, Hypervision Surgical Ltd
Aim of the PhD Project:
- Synthesis of a multimodal MRI/fluorescence Quantum Dot (QD) probe targeted for high grade glioma (HGG)
- In vitro validation of the QD probe in HGG cells
- Preclinical validation of QD probe in murine models of HGG using MRI and an intraoperative hyperspectral imaging (HSI) system
Each year, in the UK, approximately 12,100 patients are diagnosed with a primary brain tumour1 of which around 4,500 cases are gliomas. Despite advanced treatment, malignant or high-grade glioma (HGG) continues to have a poor prognosis with a median survival of 15 months and a 5-year survival of less than 5%2. Patients with HGG who undergo gross total resection of their tumour have a significantly longer survival than those with a subtotal resection3.
The extent of surgical resection must always be balanced with the risk of postoperative morbidity but even with the most advanced techniques available, it remains impossible to reliably identify tissue boundaries and surrounding normal critical structures intraoperatively. As such, difficult intraoperative decisions with life-changing consequences for patients are still based on the surgeon’s subjective visual assessment. Protoporphyrin IX fluorescence-based imaging using 5-aminolevulinic acid (5-ALA-PpIX) is the current clinical standard for intraoperative real-time surgical guidance for HGGs4. However, visualisation of malignant tissue boundaries remains unclear due to infiltration in healthy tissue, is non-quantitative due to the time-varying fluorescence effect and relies upon the surgeon’s subjective visual assessment.
MRI is a non-invasive clinically-relevant diagnostic tool that provides highly detailed images of the brain but different contrast agents are needed to highlight tumour on MRI and intraoperatively. Quantum dots (QDs) are highly luminescent, nanoparticles with superior optical properties to 5-ALA-PpIX. The possibility of combining QDs with MRI in a single tool offers the tantalising prospect of high sensitivity optical imaging with the unrivalled resolution of MRI5. This project will develop QDs targeted prostate-specific membrane antigens (PSMA) that are expressed in HGG cells6 but not in normal brain tissue7. It will also utilise the cancer cell biosynthetic pathways to produces QDs in situ as an alternative to chemical synthesis.
Advanced optical imaging techniques provide a promising solution for intraoperative tissue characterisation by detecting minute variations in QD concentration in the fluorescence spectrum. By splitting light into multiple narrow spectral bands far beyond the colour-information visible by the human eye, HSI provides rich quantitative information that can be used in combination with computational tissue optics models for objective fluorescence quantification. Using an intraoperative HSI system ready for translation into the clinic, this project will determine whether QD tools could enable surgeons to quantitatively visualise the tumour, using a single MRI/intraoperative QD agent. This will allow for more accurate planning, improving the extent of safe surgical resection.
This project will develop fully validated multimodality QD-based tools targeting HGG in preclinical models. This work could deliver improved clinical outcomes for patients, increasing primary cure rates whilst reducing the need for multiple agents, thus lowering the risk of associated side effects.
The project requires a student with a background in chemistry. Some knowledge of engineering and medical physics would also be advantageous.
- CRUK: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/brain-other-cns-and-intracranial-tumours/incidence
- M. Koshy et al. Journal of Neuro-Oncology, 2012 https://doi.org/10.1007/s11060-011-0738-7
- T. J. Brown et al. JAMA Oncol., 2016 https://doi.org/10.1093/nop/npy034
- W. Stummer et al. Lancet Oncology, 2006 https://doi.org/10.1016/S1470-2045(06)70665-9
- L.E. Jennings, and N.J. Long. Chem Commun, 2009 https://doi.org/10.1039/B821903F
- A. Holzgreve et al. Front. Oncol. 2021 https://doi.org/10.3389/fonc.2021.646387
- D.A. Silver et al. Clinical Cancer Research, 1997 http://clincancerres.aacrjournals.org/content/3/1/81.abstract