Colorectal (bowel) cancer is the second most common cause of cancer-related death in Australia, with around 16,400 new cases and 5,600 deaths expected in 2019. If detected early, bowel cancer can be cured by surgery, but once it has spread it is difficult to treat successfully. Advanced bowel cancer is often treated with chemotherapy, radiation or a combination of both, but the outcomes vary greatly.
This research team has discovered that the lack of a certain protein, called MCC (‘mutated in colorectal cancer’), causes a disruption in the function of other key proteins in the colon and this promotes the development of an invasive type of colorectal cancer. In normal cells, MCC has protective functions but can be ‘turned off’ by cancer cells so that this protection is lost in a subset of bowel tumours. Without MCC, DNA damage accumulates and the function of other protective genes needed to repair the damage is compromised. These features help the tumour grow but also expose a weakness as DNA damage can be targeted by drugs to kill cancer cells.
Professor Maija Kohonen-Corish and her team have been developing crucial evidence on MCC alteration with the aim of creating new treatment targets and biomarkers for bowel cancer.
The research team will test possible therapies in MCC-altered bowel cancer by exploiting the tumour’s vulnerability caused by DNA damage. The team will explore the effectiveness of a potential new treatment for these tumours. In the laboratory, they will test two drugs, irinotecan and PARP inhibitors. They will apply these drugs separately and in combination to cells that either have normal MCC or lack of it and compare the effects. Irinotecan is currently used to treat bowel cancer, but these experiments may provide a scientific explanation as to why some tumours respond better to this drug than others. These experiments will also show whether PARP inhibitors are likely to improve irinotecan treatment.
The team will also explore how the DNA damage accumulates in cancer cells without MCC. They will treat cells with various drugs and determine which specific cellular functions are most affected by the lack of MCC. These experiments will reveal why these tumours may have an enhanced response to cancer therapy.
The work of Professor Kohonen-Corish and her team will potentially improve the treatment of bowel cancer by introducing new drug targets and an understanding of how these targets could be better exploited to kill cancer cells. Using MCC loss as a biomarker, they will also introduce a new way to more accurately identify patients who are likely to respond to a specific treatment.