Grant: Operating Grant

Effective cancer therapy exploits specific biological differences between cancer cells and normal cells. Tumour cells often have defects that reduce the efficiency of DNA repair. Many current anti-cancer therapies, such as radiation, exploit these differences by generating DNA damage. However, DNA damaging therapies can also have side effects in non-cancerous cells. Certain drugs, in particular those that target DNA repair enzymes, can enhance DNA repair defects and increase the toxicity of DNA damage in tumour cells. We call this phenomenon "Synthetic Cytotoxicity". Synthetic cytotoxicity could result in increased killing of tumour cells relative to normal cells and allow for lower doses of DNA damaging agents, which could reduce side effects. The challenge is that there are thousands of possible combinations of drugs, DNA damaging agents, and tumour types that need to be screened to identify synthetic cytotoxic combinations. As the basic mechanisms involved in DNA repair are similar across diverse organisms, we propose to use yeast as a simple model organism to rapidly test millions of possible combinations of tumour-associated defects, drug targets, and DNA damaging agents to identify interactions. The synthetic cytotoxic interactions identified in the yeast screens will be prioritized for further testing in tumour cell cultures. The results from this study will be useful in identifying new drug targets and combination therapies that could be used for the selective killing of cancer cells in patients.