O239: Identification of novel radiosensitisers in colorectal cancer cells

Abstract Introduction Locally advanced rectal cancer is typically treated with neoadjuvant chemoradiotherapy, where chemotherapy acts synergistically to radiosensitise cancer cells. Response to chemoradiotherapy is variable, with 8-20% of cases having a complete pathological response, but 20-30% demonstrate no response or disease progression. Novel radiosensitisers can potentially improve response, tolerability of radiotherapy and de-escalate treatments, including the need for major surgery. This study aims to perform a screen of available FDA-approved drugs to identify novel radiosensitisers in rectal cancer. Methods A drug screen of forty FDA-approved drugs was performed. HCT-116 cells were cultured and treated as a monolayer with 0.3μM and 1.0μM of a specific drug for 16 hours. Clonogenic assays were performed in 24 well plates after photon irradiation at 0 and 1 Gy. Relative colony formation (survival fraction) was employed to measure drug efficacy and radiosensitisation. Following the screen, two drugs were selected for dose optimisation and further mechanistic evaluation with DNA repair kinetics and DNA damage using immunofluorescence of γH2Ax foci. Results Abexinostat and Fomepizole were selected from the screen for dose optimisation based on their radiosensitising capabilities. Dose optimisations determined both drugs had an optimal concentration of 0.5 and 1.0μM and required an optimum of 6 hours of treatment, and showed significant radiosensitisation. Prolonged DNA repair kinetics and significantly more γH2Ax foci in cells treated with Abexinostat and Fomepizole indicated persisting DNA damage. Conclusion Abexinostat and Fomepizole show promise as radiosensitizers. Further experimentation is ongoing to determine the mechanism of action for these drugs and their translational potential.