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Experimental Radiotherapeutics

Cellular responses to DNA damage induced by ionizing radiation. The responses are DNA repair, cell-cycle checkpoint activation, cell death and senescence.
Cellular responses to DNA damage induced by ionizing radiation. ROS = reactive oxygen species, SSB = single-strand break, DSB = double-strand break

The Experimental Radiotherapeutics Group focuses on understanding and exploiting the biological effects of external beam ionizing radiation and therapeutic radionuclides in solid tumours (breast, pancreas, oesophageal and colorectal cancers among others). 

Advances have included the development of an antibody-based theranostic agent to target DNA damage in vivo. This technology has potential as a clinically relevant dosimeter and as a read-out for response to genotoxic treatments such as chemotherapy and radiotherapy. A body of pre-clinical work has been published and progress towards clinical application is underway (e.g. Cornelissen B. et al. J Nucl Med. 55:2026, 2014; Shah K et al. Diagn Cytopathol. 44:141-6, 2016). 

The Group pursues strategies to deliver ionizing radiation to cancer cells while simultaneously sensitizing them to the detrimental effects of radiation. An example of this approach is a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer that exhibits dual activity by inhibiting telomerase and simultaneously promoting radiation-induced genomic DNA damage (Jackson M et al. Cancer Res. 79:4627, 2019). 

The Group has recently identified the radiosensitizing properties of certain transition metal complexes: the chemical design principles and cellular mechanisms of action to achieve synergistic effects in cancer cell killing have been reported (Gill M et al. Chem Sci, 9:841, 2017; Gill M et al. Chem Soc Rev. 48:540, 2019; Gill M et al. Chem Sci. 11:8936, 2020). 

A ruthenium-containing metallo-intercalator simultaneously inhibits DNA replication, blocks mitosis and enhances DNA-damaging ionizing radiation in oesophageal cancer cells.

A long-standing interest has been the challenge of combining external ionizing radiation with radionuclide therapy (Corroyer-Dulmont A et al. Radiother Oncol. 124:488, 2017). Accurate dosimetry is the key to enabling treatment that combines radiation from different sources and the Group has published a body of work that illuminates dosimetry at the whole-body to subcellular scales (Falzone et al. J Nucl Med. 56: 1441, 2015; Falzone et al. Theranostics. 8:292, 2018; Corroyer-Dulmont A et al. Neuro Oncol. 22:357, 2020; Abbott EM et al. J Nucl Med. 119.233650, 2020).

To be effective anticancer pharmaceuticals, including radiopharmaceuticals, must be delivered efficiently and precisely to their targets. We have tackled this challenge in two ways. First incorporation of cell-penetrating peptides (CPP) into drug design has been used to enhance cellular uptake. Second, the Group has exploited physical stimuli, primarily ultrasound, to promote tumour and intracellular delivery of radio-pharmacons (Thomas E et al. Theranostics, 9:5595, 2019; Owen J et al. 319:222, 2020).