Development of PDT/PET theranostics for Breast cancer

Primary supervisor: Graeme Stasiuk, King’s College London

Secondary supervisor: Elnaz Yaghini, UCL

Project

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 single molecule. This has the potential to inhibit tumour growth directly following diagnosis, by using the same intervention, i.e. the molecule used for imaging. The chosen imaging modality, positron emission tomography (PET), is regarded as the technique of choice for identifying and staging tumours due to its high sensitivity. To enable therapy, we will synthesise compounds known as photosensitizers, which generate highly toxic reactive oxygen species when irradiated with high intensity visible light. The technique, known as photodynamic therapy (PDT), has been shown to be highly effective for focal treatment of solid tumours with light delivered to the tumour site via fibre-optics that can be inserted inside the tumour. PDT also raises an immune response against the tumour tissue that may combat spread of the cancer.

The target cancer for this project will be Breast Cancer (BC): 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. The first intervention is surgery, but this can leave positive margins (incomplete tumour removal) so that the cancer can then spread to the lymph nodes. Novel adjuvant therapeutic tools are therefore needed to tackle BC. We hypothesize that intraoperative PDT treatment of BC guided by PET imaging can be applied to the tumour bed following surgical excision of the bulk of the tumour and thereby minimise incomplete tumour resection.

To investigate this hypothesis, the multidisciplinary project will involve chemical synthesis of the photosensitiser linked to the chelator that will incorporate the radiometal gallium-68/or manganese-52, followed by bioconjugation to a targeting peptide/antibody (e.g. trastuzamab) for BC such as for the HER2 tumour-associated antigen which is known to be overexpressed in many BC patients. This work will draw on feasibility studies from our team (see references). This will be followed by radiolabelling experiments with gallium-68 to show specific uptake into the chelator, radiochemical yield and specific activity. Once the PET/PDT agent has been made, it will be validated in HER2 overexpressing breast cancer lines (e.g. SK-BR-3, BT474) along with control tumour cell lines to demonstrate specific uptake in HER2 overexpressing tumour cells and toxicity under light irradiation. This will be followed by in vivo experiments to show the efficacy of the image guided therapeutic in preclinical tumour models with laser light delivered using an implanted fibre-optic probe.

Candidate background

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.

Potential Research Placements

1. Kerstin Sander, Centre for Radiopharmaceutical Chemistry, UCL
2. Elnaz Yaghini/ Sandy MacRobert, Surgical Biotechnology, UCL
3. Vijay Chudasama, Department of Chemistry, UCL

References

1. Bn2DT3A, a chelator for 68Ga PET: hydroxide coordination increases biological stability of [68Ga][Ga(Bn2DT3A)(OH)]-, T. W. Price, I. Renard, T. J. Prior, V. Kubicek, D. Benoit, S. J. Archibald, A.-M. Seymour, P. Hermann, G. J. Stasiuk*, Inorganic Chemistry, 2022, 61, 43, 17059-17067. https://doi.org/10.1021/acs.inorgchem.2c01992
2. Evaluation of a bispidine chelator for gallium-68 and of the porphyrin conjugate as PET/PDT theranostic agent, T. W. Price, S. Y. Yap, R. Gillet, H. Savoie, L. J. Charbonnière, R. W. Boyle*, A.M. Nonat*, and G. J. Stasiuk*, Chem. Eur. J., 2020, 26, 7602-7608.
3. Selective radiolabelling under mild conditions, a route towards a PET/PDT theranostic agent, S. Y. Yap, T. W. Price, H. Savoie, R. W. Boyle* and G. J. Stasiuk*, Chem. Commun., 2018, 54, 7952-7954
4. Site-selective multi-porphyrin attachment enables the formation of a next-generation antibody-based photodynamic therapeutic. A. Maruani, H.Savoie, F.Bryden, S. Caddick, R. Boyle and V. Chudasama Chem. Commun., 2015,51, 15304-15307
5. Combination of verteporfin-photodynamic therapy with 5-aza-2′-deoxycytidine enhances the anti-tumour immune response in triple negative breast cancer. Banerjee SM, Acedo P, El Sheikh S, Harati R, Meecham A, Williams NR, Gerard G, Keshtgar MRS, MacRobert AJ, Hamoudi R. Front Immunol., 2023, 14:1188087. doi: 10.3389/fimmu.2023.1188087.