Targeting the Guardian of the Genome (Professor Justin Stebbing)
The protein p53 was first discovered in 1979 and has earned the name 'the guardian of the genome' due to its crucial role in controlling the growth of cells and, more importantly, preventing the growth and spread of abnormal or cancerous cells and causing them to die. A number of changes must occur within a normal cell for it to become cancerous, but it is now clear that the development of abnormal p53, or loss of its production, is the single most important step in this process.
As long as a cell maintains a normally functioning p53 protein, it preserves its ability to stop growing or 'self-destruct' if other cancer promoting changes occur, and therefore it prevents cancer from growing or spreading. However, if p53 function becomes abnormal, a cell's ability to self-regulate its growth is lost, and cancer can therefore develop and spread. Furthermore, as many traditional anti-cancer drugs require p53 to function normally for them to have an anticancer effect, this loss of p53 also significantly contributes to drug resistance in patients' tumours. In fact we now know that tumour cells in up to 90% of all patients with cancer have an abnormality in the p53 protein and much effort has been focused on the development of drugs that could cure cancer by replacing the lost p53 in tumours or targeting the abnormally functioning p53. However, to date, all of these drugs have been unsuccessful and few have made their way into the cancer clinic.
p53 functions in cells by controlling the production of genes involved in preventing cancer, but is also itself controlled by other genes and small molecules in cells called microRNAs. MicroRNAs are tiny pieces of genetic material that also control the level and activity of genes controlled by p53 and the genes that control p53. Therefore we believe that understanding the role of p53-associated microRNAs, and their gene targets, will enable us to develop new drug treatments that can repair the effects that the loss of p53 function has on cancer cells.
We want to determine whether any microRNAs could be delivered to cancer cells as a surrogate for p53 and replace the lost function of p53 in those cells. These experiments will utilise new techniques and once we have identified which microRNAs may function in this way, we will perform experiments to confirm that our findings are actually relevant to human patients with cancer. If this is successful, we will work with our colleagues in the chemistry and pharmaceutical departments to develop a drug to allow us to deliver the identified microRNAs to tumours with deficient p53, and thereby to replace its function. Because p53 is the most commonly abnormal gene in so many cancers, targeting this is almost certain to have applicability in most tumour types.
Despite p53's importance, no one has 'cracked' how to target it therapeutically. This work represents a dynamic new approach to one of the oldest problems in cancer medicine. Our goal here is to target one of the most important molecules inside cells, to block it, using a simple method that has never been attempted before. We believe we can do all of this, and make a massive, life-saving difference.