Current clinical care of cancers typically relies on imaging of the tumour for diagnosis and therapeutic interventions (surgery, chemotherapy, radiotherapy) to be performed separately, sometimes several weeks apart. Critically, during this time, the tumour has the opportunity to grow and spread. In this project, we seek to combine both imaging and therapy into a match paired theranostic treatment. This has the potential to inhibit tumour growth directly following diagnosis, by using the same intervention, i.e. with different isotopic element (212Pb/203Pb) for imaging and therapy. The chosen imaging modality, positron emission tomography (PET), is regarded as the technique of choice for identifying tumours due to its high sensitivity. To enable therapy, we will use molecular radiotherapy from a beta/alpha emitting isotope. Theranostics is the combination of therapy and diagnostic imaging in one tool. Nuclear medicine has currently adopted a theranostic “matched pair” radioisotopes approach, the gold standard is with 68Ga (PET) 177Lu (therapy).There is a difference in biodistribution of the imaging tracer and the radionuclide therapy, due to the difference in coordination chemistry between 68Ga and 177Lu requiring different chelators, thus presenting issues with dosimetry, and efficacy of the treatment.In contrast this project will utilise a “true theranostic pair” in which two radionuclides of the same element are used (44/47Sc, 64/67Cu, 203/212Pb). This approach has the advantage of providing the exact same biodistribution between the imaging and therapy to ensure accurate diagnosis, dosimetry, and monitoring of disease progression.
The MRT will be targeted to Fibroblast Activation Protein Inhibitor (FAPI), targeting the FAP, which is known to be highly expressed in the major cell population in tumor stroma, termed cancer-associated fibroblasts. We will study this MRT in Breast cancer (BC) a model cancer: approximately 55,500 patients are diagnosed per annum in UK with BC and 1 in 7 women in the UK develop BC in their lifetime. A novel adjuvant therapeutic tools are therefore needed to tackle BC.
To investigate this hypothesis, the multidisciplinary project will involve chemical synthesis of novel chelators that will incorporate the radiometal (44/47Sc, 64/67Cu, 203/212Pb), followed by bioconjugation to a FAPI targeting motif. This work will draw on feasibility studies from our team. This will be followed by radiolabelling experiments to show specific uptake into the chelator, radiochemical yield and specific activity. Once the theranostic/MRT agent has been made, it will be validated in FAP overexpressing breast cancer lines along with control tumour cell lines to demonstrate specific uptake in overexpressing cells and toxicity/radiobiological effect of the MRT. This will be followed by in vivo experiments to show the efficacy of the therapeutic in preclinical tumour models.
The project is suitable for a student with background in organic chemistry and a strong interest in life sciences, in particular oncology. The student will be able to gain new interdisciplinary skills such as radiochemistry, cell culture, in vivo preclinical imaging, and acquire expert knowledge in basic medical science research.
For further details and to apply please visit the studentship webpage.
