By genetically manipulating and removing the most common mutant form of the p53 gene that promotes colorectal cancer in humans, an international team of scientists has demonstrated that this therapy reduces tumour growth and tissue invasion. The research was led by Dr Ute Moll, Professor and cancer biologist in the Department of Pathology at Stony Brook University School of Medicine, the findings published in Cancer Cell.
Specific 'hotspot' mutations of p53 have recently been recognized as strong promoters of cancer in humans, about 60 percent of colorectal cancers harbour p53 mutations. The challenge for scientists has been discovering whether and which mutant forms of p53 are best to target - and in which tumour entity - in order to halt the cancer process or slow it down. In this study, Dr Moll and colleagues assessed one of the three most common p53 mutants in colorectal cancer - mutp53 R248Q, exchanging an Arginine (R) for a Glutamine (Q) - in a high fidelity genetic mouse model of the disease.
The researchers found that therapeutically ablating the mutant p53 gene in mice that had developed colorectal cancer markedly inhibited tumour growth and reduced tumour invasiveness by 50 percent. As an underlying mechanism they identified that the mutant p53 protein (produced from its corresponding gene), which is highly stabilized in the tumour cells, binds to and activates Stat3, a key tumour promoter. This promotes cancer progression and correlates with poor outcomes in humans and mice.
The researchers demonstrated that Stat3 activation via the mutant p53 protein mediates tumour growth and invasion. They also showed that many human cancer entities including gastrointestinal cancers with R248 mutations are associated with poorer patient survival compared to those with nonR248 mutations of p53.
Moreover, the researchers found that genetic deletion of mutant p53 was only one way to slow down tumour growth and progression. They also discovered that inhibiting the folding chaperone enzyme Hsp90 - which they discovered earlier to be responsible for mutant p53 protein stabilization - by a small molecule drug called 17AAG, Stat3 signalling, tumour growth and progression of mutp53-driven tumours were equally stopped.
"We discovered that in p53-mediated colorectal cancer driven by the most common mutant form of p53, there is an exploitable tumour dependence on continued expression of the mutant protein for the tumours to thrive," said Dr Moll. "Our data suggest that this and similar p53 mutants represent actionable drug targets responsive to treatment by removal, for example with Hsp90 inhibitors.”
Dr Moll and colleagues will expand on this research and conduct experiments in other tumour entities in her new cancer laboratory located in Stony Brook University's soon-to-open Medical and Research Translation (MART) Building.