Grant: Undergraduate Student Research Awards (USRA)

Radiation therapy is one of the main approaches in the treatment of solid tumours. Many of the factors that influence the tumour response to radiation have been characterized and exploited to maximize the response to radiotherapy among different patients. The mechanism of cancer cell death induced by ionizing radiation (IR) involves both genomic (DNA damage) and non-genomic effects. The latter is often associated with the generation of reactive oxygen species, which induce an iron-dependent form of cell death called Ferroptosis. Ferroptosis is promoted by free intracellular iron, high glucose, and by the presence of poly-unsaturated fatty acids (PUFAs), and is opposed by isoprenol, squalene, sterols and cholesterol. Using well established pharmacological interventions based on statins and nutritional interventions based on cholesterol-deprived media, we will examine the effects of lowering isoprenoid synthesis on tumour cells' sensitivity to ferroptosis and IR-induced cell damage. The experiments will make use of breast cancer and lung cancer cell lines which will be genetically or metabolically programmed to promote or reduce their resistance to Ferroptosis. The modified cells will then be exposed to X-rays (0.1-2 Gy) and their survival will be evaluated via viability and/or clonogenic assays. Gene expression studies will then be employed to evaluate the pathways affected by the intervention. Data analysis will be used to ensure reproducibility and rigor of our studies. All data will be deposited in public databases and the results will be communicated for publication.