Targeting novel regulators of nucleotide metabolism to treat cancer

1 in 2 people will be diagnosed with cancer in their lifetime. Despite modern medical advancements, cancer is the leading cause of death in the western world. Metabolism is commonly altered in cancer cells, and many mainstream chemotherapeutics work by targeting metabolism (e.g. 5-fluorouracil and methotrexate). Anti-metabolites disrupt nucleotide synthesis, resulting in depletion of nucleotides and replication stress, which causes cells to die. Cancer cells typically have higher rates of replication, making them more sensitive to anti-metabolites. However, normal cells are still affected, and the use of these drugs in cancer is limited by toxicity to normal cells.

We have developed novel inhibitors to a cancer-specific enzyme, MTHFD2, involved in nucleotide metabolism required for DNA repair. We hypothesise that MTHFD2 inhibitors will selectively kill cancer cells while non-malignant cells will be unaffected.

This project will investigate the anti-cancer effects of MTHFD2 inhibitors in combination with chemotherapeutics, in particular drugs targeting the DNA damage response in vitro and in vivo. This will identify synergistic or synthetic lethal drug combinations to guide clinical translation.