Posted: 15th July 2019
Cancer starts with DNA damage.
This damage occurs randomly and constantly – simply as a consequence of our daily lives – because of aging, exposure to radiation, environmental carcinogens and other factors.
Luckily, our cells have a number of different methods to repair DNA damage. However, if it is not repaired, or repaired incorrectly, the mutations that arise can lead to the development of cancer.
Maddie Riewoldt's Vision Fellow, Dr Wayne Crismani, from SVI’s Genome Stability Unit, aims to find new treatments for people who have ‘cancer in the family’, caused by inherited mutations in the BRCA1 and BRCA2 genes.
Wayne and an international team of collaborators were recently awarded an NHMRC grant to fund the research project.
Related research in his group, on inherited bone marrow failure, is supported by funding from Maddie Riewoldt's Vision.
Wayne says that BRCA1/2 normally protect our cells from cancer by mending DNA as it is damaged.
“Nearly every cell in our bodies has two copies of each gene – one from our mother and one from our father. Some unlucky people inherit a defective copy of BRCA1/2, and then their other ‘healthy’ copy acquires a mutation that stops it from working. In these cells, BRCA1/2 can no longer fix DNA damage. This causes mutations to accumulate, leading to cancer.”
A new drug treatment, known as PARP inhibitors, introduced in 2018, works by specifically targeting those cells in which BRCA 1/2 no longer works. This concept is known as synthetic lethality.
Wayne explains, “Imagine you are riding a bike downhill, hurtling towards a busy intersection. If you pull on your handbrakes, you come to a stop. If either your left or right handbrake didn't work, you would still manage to stop to avoid a collision, but if both were faulty, you would have a bad accident.” Wayne says that a cell in which BRCA1/2 is not working has the equivalent of a faulty brake. These cells are predisposed to cancer. PARP inhibitors work by selectively knocking out the other brake – targeting an alternate way that our cells repair DNA. With both options for DNA repair gone, catastrophic damage to its DNA causes the cancer cell to die.
“However, relapse during PARP inhibitor treatment has already been seen in the clinic, because cancers are very good at evolving. This is why clinicians talk about using first-line, second-line and third-line therapies. We urgently need other drugs to treat advanced disease,” says Wayne.
Wayne is working to develop a new set of compounds that act in the same way as PARP inhibitors, but on a different arm of the DNA repair pathway, one in which he is an expert.
By exploiting DNA damage – the very thing that starts cancer in the first place – Wayne and his team hope to be able to find new ways to treat it.