Reactivating the world’s most studied gene
What’s the most popular gene in the human genome? This question was the subject of a news article in the science magazine Nature last year, in which it was reported that researchers had analysed the scientific record to compile a list of the most studied genes of all time. And topping the list? A gene called TP53 – a gene that some would say is the most important for preventing cancer.
TP53 – nicknamed the “guardian of the genome” – carries the instructions that cells need to build a protein called p53. This protein connects many molecular communication networks within a cell, sort of like a central telephone exchange receiving calls and connecting them to the right recipient. Because of this central role, p53 is able to control many key cellular functions, including several that, when broken, can lead to the development of cancer.
The normal roles of p53 include several that prevent the formation of cancer, such as activating molecular machinery that repairs cancer-causing damage to DNA, stopping cells from dividing to prevent harmful genetic mutations being passed on to the next generation of cells, and switching on the process that kills potentially harmful cells. It’s unsurprising then that genetic mutations to TP53 that mess up how the p53 protein works are common in tumours. In fact, over 50% of all cancers carry a mutation to the gene.
In many cases of cancer where TP53 is mutated, the p53 protein is still produced by cancer cells but because the instructions are wrong, the protein is built incorrectly. This often leaves p53 helpless when it comes to carrying out its anticancer functions. Finding a way to repair or “reactivate” the faulty p53 protein is an attractive prospect for cancer therapy, not least because of the number of tumours that have the potential to be treated with this type of treatment.
Since 2014, Worldwide Cancer Research has been funding Professor John Spencer at the University of Sussex, and co-workers in Cambridge and Frankfurt, to design and develop chemical compounds that can reactivate p53 in cancer cells. Just this week, it was announced that Spencer was awarded further funding to pursue this avenue of research for another two years due to the exciting progress his team has made.
Spencer has focussed his efforts on designing a drug molecule that targets a particular type of fault in how the p53 protein is built by cancer cells. The dodgy instructions encoded in the mutated TP53 gene results in a p53 protein that is essentially missing a brick in the wall. And like a game of Jenga, if you pull out the wrong brick, the whole tower crumbles to pieces. Spencer explains:
“The problem with this particular p53 is that a single amino acid, the building blocks of proteins, is changed from a tyrosine to a cysteine. The smaller cysteine no longer fits perfectly in the structure of the protein and leaves a small crevice, which causes the protein to become less stable. It (p53) basically collapses at body temperature, breaks down, rendering the guardian of the genome out of the equation and not able to police faulty cancer cells”.
Spencer’s drug molecules are designed to stabilise p53 by plugging this tiny crevice in the protein. So far the team have developed a library of molecules that are able to reactivate this version of p53. The next stage of their work will be to identify the compounds from their library that are the most likely to succeed in becoming a new cancer drug. The prospects are pretty exciting:
“In theory, a patient could be screened to see if their tumour carries this faulty version of p53 and then given a stabilising drug alongside standard chemotherapy. Because the lack of a normal p53 allows cancer cells to survive when they shouldn’t, the two treatments would act beneficially together, allowing cell death pathways to be activated in cancer cells in the face of toxic chemotherapy” explained Spencer.
“But we have to keep our feet firmly on the ground. We're a way off from this and our initial hope is to generate a compound that might interest a Pharma company, who could then look to develop it further.
So, over the next couple of years the team aims to identify the chemical compounds from their library that are the most likely to succeed in becoming a new cancer drug. They will test the toxicity of the drugs to help make sure that negative side effects are reduced, they will test the selectivity of the drugs to ensure that the ones they pick are targeted towards cancer cells with the faulty p53 and won’t harm normal cells, and they will find ways to improve the chemical structure of the drugs so that they can be as effective as possible. Ultimately, this research could lay the foundations towards the future development of a brand-new drug capable of targeting a wide range of cancers.