1st Supervisor: Graeme Stasiuk, King’s College London
2nd Supervisor: Samantha Terry, King’s College London
Additional Supervisor: Philip Blower, King’s College London
Clinical Champion: Anthony Kong, King’s College London
Aim of the PhD Project:
- Develop a positron emission tomography tracer selective for manganese
- Validate role of manganese in radioresistant tumour cell lines.
- Investigate localisation and level of manganese in tumours showing radioresistance in vivo using PET and MRI
Project Description / Background:
Manganese (Mn) is an essential transition metal with a variety of biological functions; it is a cofactor to many metalloenzymes, non-enzymatic antioxidants and enzymatic activation, and a change in its homeostasis gives rise to a variety of different diseases. One of the key functions of manganese is as a cofactor to super oxide dismutase (SOD), an enzyme that protects the cell from free radicals and DNA damage. Manganese is thus crucial in maintaining cell viability. It has also been shown that there is an increase in intracellular SOD levels within radioresistant tumours. This in turn leads to a large influx of free Mn within the cell to accommodate the high SOD expression levels, it is also proposed that free Mn also has SOD activity itself. Therefore, it is proposed that Mn could be used as a biomarker of tumour radioresistance and reoccurrence, presenting a powerful tool for predicting radiotherapy efficacy in patients. Determining why some tumours are radiosensitive, while others return after radiotherapy, requires new non-invasive non-traditional approaches to oncology. Positron emission tomography (PET) is a powerful non-invasive clinical imaging tool with high sensitivity and specificity with a long history of cancer diagnosis with 18F-FDG and presents an excellent modality for understanding Mn localisation and concentration in vivo. Mn(II) is also MR active changing the relaxivity of local water protons, changing local MR signal. It is proposed that at the level of free Mn(II) present in the most radioresistant tumours it will also be detectable by MRI, so this modality will be used to confirm localisation within the tumour and evaluated as an imaging biomarker for radioresistance. This PhD project sets out to synthesise a positron emission tomography tracer specific for Mn to understand in vivo the relationship between radioresistance in tumours and manganese. This will be in several stages:
- Tracer synthesis and specificity for Mn over other metals: Including chelator design, with appropriate donor atoms and coordination geometry, hepta-or hexadentate ligands with N and O coordinating atoms, UV-Vis and fluorescent studies for affinity.
- Radiolabelling with fluorine -18: Validating radiochemical yield, molecular activity and serum stability.
- In vitro studies to show cell uptake in a variety of cell lines incubated with different Mn levels, in both radiosensitive and radioresistant tumour types. This includes developing cell culture techniques and radioresistant cell lines.
- In vivo studies to show tracer uptake in Mn rich tissues and comparing radiosensitive tumours with radioresistant tumours: dynamic PET scanning in subcutaneous murine models.
- MRI experiments in vivo to validate probe uptake with Mn(II) localisation
- ICPMS and SOD expression levels as markers of Mn concentration on tumour tissues.
The development of a Mn -specific PET tracer will provide a powerful tool in predicting radioresistance in tumours, allowing for a greater understanding of radioresistance in tumours and giving wider choices prior to therapy, for better patient outcome. This work builds upon our groups’ prior research experience in the development of zinc sensors for PET, MRI and fluorescence as well as radionuclide imaging of radiotherapy response. This project also aligns with a current PhD project using the radioisotope 52Mn, to monitor Mn trafficking in radiotherapy resistant cancers. The PhD candidate will be expected to have a degree in chemical sciences, biochemistry or cancer biology with a willingness to undertake organic chemistry, radiochemistry, tissue culture and in vivo studies.
Figure 1: Scheme showing a Mn(II) sensor with PET identifying high levels of Mn in radioresistant tumours. In the diagnosis of radioresistance.